Facile one-pot synthesis of 2-aryl-substituted nitriles and 2-aryl-3-keto nitriles via benzyne reaction

Article abstract of DOI:10.1080/00397910600943402

2-Aryl-substituted nitriles were prepared in good to excellent yields in a one-pot reaction by the reaction of benzyne, generated using neutral conditions from (phenyl)[o-(trimethylsilyl)-phenyl]iodonium triflate, and 2-lithionitriles. 3-Keto nitriles substituted at the 2-position were obtained in good yields when these reactions were trapped with acid chlorides. The mechanism of the benzyne reaction in terms of a N-lithiobenzocyclobutanimine intermediate is discussed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600943402

This article was downloaded by: [Pennsylvania State University]
On: 22 February 2013, At: 03:41
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Facile One‐Pot Synthesis of 2‐Aryl‐substituted
Nitriles and 2‐Aryl‐3‐keto Nitriles via
Benzyne Reaction
Sukanta Kamila a , Benjamin Koh a & Edward R. Biehl a
a Southern Methodist University, Dallas, Texas, USA
Version of record first published: 24 Nov 2006.
To cite this article: Sukanta Kamila , Benjamin Koh & Edward R. Biehl (2006): Facile One‐Pot Synthesis of
2‐Aryl‐substituted Nitriles and 2‐Aryl‐3‐keto Nitriles via Benzyne Reaction, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:23, 3493-3507
To link to this article: http://dx.doi.org/10.1080/00397910600943402
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 36: 3493–3507, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600943402
Facile One-Pot Synthesis of 2-Aryl-
substituted Nitriles and 2-Aryl-3-keto
Nitriles via Benzyne Reaction
Sukanta Kamila, Benjamin Koh, and Edward R. Biehl
Southern Methodist University, Dallas, Texas, USA
Abstract: 2-Aryl-substituted nitriles were prepared in good to excellent yields in a one-
pot reaction by the reaction of benzyne, generated using neutral conditions from
(phenyl)[o-(trimethylsilyl)-phenyl]iodonium triflate, and 2-lithionitriles. 3-Keto
nitriles substituted at the 2-position were obtained in good yields when these
reactions were trapped with acid chlorides. The mechanism of the benzyne reaction
in terms of a N-lithiobenzocyclobutanimine intermediate is discussed.
Keywords: benzyne, nucleophilic addition, Dials-Alder reaction, (phenyl)[o-tri-
methylsilyl)-phenyl]iodonium triflate, 2-aryl substituted nitriles
INTRODUCTION
During our studies on the use of nitrilases as biocatalysts in the room-
temperature hydrolysis of nitriles to carboxylic acids, we needed several
2-arylalkanedinitriles, 2-aryl-3-ketotonitriles, and 3-aryl-2-hydroxyalkaneni-
triles. As shown in Fig. 1, 2-aryl-substituted nitriles are very important
building blocks for synthesizing pyridine, carboxylic acids, primary amines,
bicyclic amidines, lactones, aldehydes, and esters.[1] These nitriles are also
valuable for constructing biologically active compounds verapamil (1)[2]
and 3-alkylated-3-(4-aminophenyl) piperidine-2,6-diones (2).[3]
Compound 1 acts as a slow-acting calcium channel antagonist, and
compound 2 has shown promise in many trials with postmenopausal and
ovariectomized premenopausal women.[4–8]
Received in the USA May 9, 2006
Address correspondence to Edward R. Biehl, Southern Methodist University,
Dallas, TX 75275, USA. E-mail: ebiehl@smu.edu
3493

3494
S. Kamila, B. Koh, and E. R. Biehl
Figure 1. Typical biologically active compounds prepared from 2-aryl nitriles.
The classical way of preparing 2-aryl-substituted nitriles involves the
displacement of an activated benzylic alcohol or halide with potassium
cyanide at elevated temperatures, followed by 2-alkylation.[3,9] The benzyne
reaction, however, provides 2-arylalkanenitriles in a more efficient one-pot
reaction under less drastic conditions.[10] Typically, a benzyne intermediate
is generated by the reaction of a haloarene with a strong base such as
sodium amide or lithium diisopropyl amide (LDA) at low temperatures in
the presence of freshly prepared 2-lithiated alkanenitrile. This anion then
adds to benzyne to give 2-arylalkanenitrile, after proton quench. Although
the base-mediated benzyne reaction provides 2-arylalkanenitriles under very
mild conditions, the nitrile yields are negatively impacted by several pesky
side reactions. These include amination of benzyne by the basic amine;
reductive debromination of the haloarene, especially in the case of bromo-
and iodobenzenes;[11] and the formation of di- and triarylalkanenitriles.
Recently, we[12] synthesized a variety of fused heterocycles by generating
benzynes from the efficient hypervalent iodine benzyne precursor, (phenyl)
[o-trimethylsilyl)-phenyl]iodonium triflate (3),[13] with Bu4NF (TBAF) in
the presence of heterodienes. Because the aforementioned side reactions
were absent, the fused heterocycles were obtained in excellent yields
(.80%). We have now extended this TBAF-mediated reaction to the
synthesis of titled compounds and report the results herein.
RESULTS AND DISCUSSION
As shown in Scheme 1, a super-dry THF solution of iodonium triflate (3) and
2-lithionitrile (7), prepared by the reaction of 6 and n-BuLi, was cooled to
2408C. TBAF (4) was then added dropwise, and the resulting solution was
allowed to warm to room temperature, during which time benzyne (5) was

Facile One-Pot Synthesis via Benzyne Reaction Nitriles
3495
Scheme 1.
formed and subsequently trapped by 7a–g to give the appropriate a-aryl-
alkanenitrile 8a–g after an ammonium chloride quench.
As shown in Table 1, the yields of 8a–e ranged from essentially quantitat-
ive (entries 1–3) to good (entry 4, 85%) to modest (71% 5, 73%). The yields of
dinitriles 8f, g (entries 6 and 7) are modest (71% and 60%, respectively) but are
actually quite good when compared to those prepared by the classical benzyne
method, which gives mainly intractable tars. Further, other nonbenzyne pro-
cedures generally require longer reaction times, higher temperatures, and/or
more stages. For example, the anaerobic, solid-supported Ru-catalyzed prep-
aration of 8e requires heating at 20 h at 1808C,[14] and the preparation of 8f
by the cross-coupling reaction of bromobenzene and malonitrile requires
stirring at 158C for 12 h[15] or at 858C for 10 h.[16]
To see if 2-lithioarylacetonitriles might also react with 5 to give
2-arylated nitriles, we generated benzyne (5) from 3 and trapped it with
2-lithiophenylacetonitrile. However, as shown in Table 1 (entry 8), the
rearranged 2-benzylbenzonitrile (8 h) was obtained in 71% yield. This was
surprising in that we had previously found that arynes lacking electron-
donating groups reacted with 2-lithioarylacetonitriles to give mainly unrear-
ranged 2-arylacetonitriles.[17] However, we had not studied the reaction of
benzyne itself with 2-lithiophenylacetonitrile. Thus, we repeated this
reaction under classical benzyne conditions (PhBr/PhCH2CN/LDA in
THF) and (as shown in Scheme 2) obtained a mixture 8 h (21%) and 2,2-
diphenylacetonitrile (47%). Thus, our benzyne method reported here should
prove valuable for the synthesis of 2-benzylbenzonitriles, which are
important precursors to 9-amino analogs arylnapthofuranone ligan
derivatives.[18]
We next carried out the reaction of benzyne (5) with 2-lithionitriles 7a–h
and trapped the aryne–nitrile anion adduct with a variety of electrophilic
trapping reagents, the results of which are shown in Table 2.

3496
S. Kamila, B. Koh, and E. R. Biehl
Table 1. a-Lithionitriles 8 by NH4Cl quench of reaction 7 with 5
Entry
1
a-Lithionitrile 7
NCCH2Li a
a-Arylnitrile 8
Yield (%)
.99
a
2
3
NCCH(Me)Li b
NCCH(Et)Li c
.99
.98
b
c
4
NCCH(prop)Li d
85
d
e
5
6
NCCH(Bu)Li e
(CN)2CHLi f
71
73
f
7
8
NCCH2CH(CN)Li g
PhCH(CN)Li h
60
71
g
8 h
We first studied the effect of the nature of the trapping reagent on the
product distribution using iodobenzene (9a) and MeOD as electrophilic
precursors. Thus, when the reaction of benzyne (5) with 2-lithioacetonitrile
(7a) (entry 1) was trapped with iodobenzene (9a) (which was added prior to
benzyne generation at 2308C), a 1 : 1 mixture of 2-iodophenylacetonitrile
(10a) and 2-iodophenylacetonitrile (10b) was obtained. However, when 5
was treated with 7b and subsequently quenched with MeOD, compound 10c
was obtained in 99% yields. The structure of 10c was confirmed by the
1
appearance of a singlet for the methyl hydrogens in its H NMR spectrum.
Scheme 2.

Facile One-Pot Synthesis via Benzyne Reaction Nitriles
3497
Table 2. Electrophilic trapping reactions yielding 10
Entry
1
7 R
Trapping agent 9
Trapped nitrile 10
Yield (%)
H
PhI
a
36
36
a
b
c
2
3
Me
H
MeOD
b
99
78
c
d
e
f
4
5
6
Me
Et
H
60
67
81
d
e
f
g
7
8
Me
H
79
84
f
h
g
i
i
j
9
H
71
10
Me
c
i
k
(continued)

3498
S. Kamila, B. Koh, and E. R. Biehl
Table 2. Continued
Entry
11
7 R
Trapping agent 9
Trapped nitrile 10
Yield (%)
68
H
l
j
j
12
13
14
Me
H
79
81
79
m
n
k
k
k
Me
o
15
16
CH3CH2CH2
82
79
p
Me
l
q
r
17
18
19
H
H
H
78
a
m
n
s
b
o
t
aCompound 10s was prepared by NaBH4 reduction of 10j in 91% yield.
bCompound 10t was prepared by NaBH4 reduction of 10l in 77% yield.
cCompound 10k was not formed; only a-arylnitrile 8b was obtained.

Facile One-Pot Synthesis via Benzyne Reaction Nitriles
3499
This indicated that the initially formed aryne–nitrile anion, which possesses a
negative charge on the carbon adjacent to the cyano-containing side chain
adduct (11), isomerized to the 2-lithionitrile (16) during the course of the
reaction (see Scheme 2).
When the reactions of 5 with 2-phenylacetonitriles (7a–c) were trapped
with acid chlorides (9c–m) (entries 3–17) the respective b-keto nitriles
10d–r were obtained in overall yields of 60–84%. Many of the products are
known compounds. The structures of the novel compounds were ascertained
1
by H NMR, 13C NMR, and elemental analysis. The reactions involving
2-lithioacetonitrile produced 3-ketonitriles. This rapid one-pot synthesis of
the 3-ketonitriles under mild conditions, with one exception,[19] is superior
to other methods that require harsher conditions (e.g., the synthesis of 10 g
[entry 6] requires heating at 658C for 2 days)[20,21] and/or are limited to the
synthesis of b-ketonitriles unsubstituted at the 2-position.[22] In the exceptional
case,[19] primary and secondary nitriles are acylated with N-acylbenzotriazoles,
which are prepared from carboxylic acids. The nitriles are deprotonated using
either n-butyllithium at 2788C or t-BuOK in DMSO at 258C. In the former
case, N-acylbenzotriazoles are added, and resulting solution is stirred at
2788C for 2 h, then warmed to room temperature. In the latter case, the
triazoles are added, and the resulting solution is stirred an additional 12 h.
Although these procedures give slightly higher yields, the procedure reported
here has the advantages of using acid chlorides, many of which are commer-
cially available, and a quicker reaction time.
Unfortunately, attempts to trap the reaction of 5 and 7a with heteroaro-
matic aldehydes 9n and 9o failed to give the corresponding nitrile alcohols
10s and 10t (entries 18 and 19). However, these alcohols were obtained by
reduction of 10j and 10l with NaBH4 in 91% and 77% yields, respectively.
Interestingly, when the reaction of 5 and 7a was trapped with 1-H-
pyrrole-2-carbonyl chloride (9 m), Z-2-phenyl-3-1-H-pyrrol-2-yl)acrylonitrile
(10r) was obtained in 78% (entry 17). Apparently, under these conditions, the
latter was obtained by hydrolysis of the corresponding alcohol.
Our studies reported herein support the mechanism put forth by
Meyers[23] and further refined by Durst.[24] As shown in Scheme 3, benzyne
(5) reacts with 7 to give the initial adduct 11, which closes to the N-lithioben-
zocyclobutanimine intermediate 12 in the case of R ¼ alkyl or to 13 in the
case of R ¼ Ph. Durst has shown that all benzyne reactions involving nitrile
anions proceed through the four-membered ring intermediate 12 or 13.[24] Fur-
thermore, the direction of opening of 12 and 13 is governed by the relative
stability of resulting open chain anions. In the case of 13 (R ¼ phenyl), the
ring opens to the more stable rearranged nitrile 14 in which the negative
charge is delocalized over two aromatic rings. Proton quench 14 with
ammonium chloride then gives 8 h. However, the intermediate ring 12
(R ¼ alkyl) reverts back to 11 rather than to the rearranged anion 15. In this
case, rearranged anion 15 is less stable than 11 because the negative charge
on the 2-carbon in 15 is destabilized by the alkyl electron-donating group.

3500
S. Kamila, B. Koh, and E. R. Biehl
Scheme 3.
As the reaction proceeds, 11 isomerizes to the more stable anion 16, which is
stabilized by resonance interactions between the adjacent phenyl and CN
groups. Thus when the PhI electrophile is added to the reaction mixture
prior to benzyne formation, both 11 and 16 are trapped by PhI to give 10a
and 10b, respectively. However, when the trapping agent is added at the
end of the reaction, compound 11 completely isomerizes to 16, which then
is trapped by the acid chloride to give the products 10c–i.
This mechanism also provides an explanation of why Meyer’s method
gives rearranged nitriles rather than typical aryne products from the reaction
of 2-lithiated alkanenitriles. As shown in the Scheme 4, the N-lithiobenzo-
cyclobutanimine intermediate 12a formed in the reaction of 3-oxazolidinyl-
substituted benzynes preferentially opens to the rearranged anion 15a
because of a stabilizing complex-induced proximity effect (CIPE)[25] effect
between the lithium ion and nitrogen atom of the oxazoline ring.
In conclusion, we have developed a convenient, one-pot, high-yield
synthesis of 2-aryl-substituted nitriles and dinitriles that involves generating
arynes under neutral conditions in the presence of preformed 2-lithiated
nitriles. The yields of these reactions are significantly higher than those
prepared under base-mediated benzyne reactions. In addition, several
3-keto-2-arylnitriles were obtained in good overall yields when benzyne
was similarly generated and trapped with acid chlorides.

Facile One-Pot Synthesis via Benzyne Reaction Nitriles
3501
Scheme 4.
EXPERIMENTAL
Melting points and boiling points were taken on a Mel-Temp capillary
1
apparatus and are uncorrected with respect to stem correction. H and 13C
NMR spectra were recorded on a 400-MHz Bruker Advance DRX-400 multi-
nuclear NMR spectrometer. Chemical shifts are reported in reference to TMS
as internal standard. Elemental analysis was obtained from Southern
Methodist University Analytical Service Laboratories. All chemicals were
purchased from Fisher Scientific, VWR, or Aldrich Chemicals.
General Procedure for the Synthesis of 2-Arylnitriles
and 2-Aryldinitriles
To a well-stirred solution of THF (5 mL) and n-BuLi (1.6 M, 1.2 eq) kept at
–788C, a solution of nitrile (1.5 eq) or dinitrile in THF (5 mL) was slowly
added through needle syringe system. After stirring for 15 min at that tempera-
ture, the solution was allowed to warm at 2408C. Then a solution of (phenyl)-
[o-(trimethylsilyl)phenyl]iodonium triflate (0.5 g, 1.0 mmol) in superdry THF
(5 mL) was added dropwise followed by Bu4NF (1.0 M, 1.3 mL, 1.4 eq.).
Then the solution was allowed to warm at 08C and kept for 15 min. After
stirring for another 40 min at rt, a solution of ammonium chloride (1 g/ mL
H2O) was added. The resulting solution was extracted with dichloromethane
(2 ꢀ 5 mL), washed with brine, and dried (Na2SO4). Evaporation of the
solvent afforded the crude compound, which was then purified by column
chromatography using ethyl acetate–hexane (9 : 1, v/v) as eluent. All the
products reported were synthesized following the same procedure.
Data
Phenyl-acetonitrile (8a). This compound is commercially available.
2-Phenyl-propionitrile (8b). This compound is commercially available.
2-Phenyl-butyronitrile (8c). This compound is commercially available.

3502
S. Kamila, B. Koh, and E. R. Biehl
1
2-Phenyl-pentanenitrile (8d). Separated as brownish oil. The H NMR and
13C NMR spectra are similar to those previously reported.[19]
1
2-Phenyl-hexanenitrile (8e). Separated as colorless gummy liquid. The H
NMR and 13C NMR spectra are similar to those previously reported.[26,27]
2-Phenyl-malononitrile (8f).[19] Separated as reddish brown gummy liquid.
The 1H NMR and 13C NMR spectra are similar to those previously reported.
1
2-Phenyl-succinonitrile (8 g). Separated as reddish color oil. The H NMR
and 13C NMR spectra are similar to those previously reported.[3]
2-Benzyl-benzonitrile (8 h). Brown-colored gummy liquid. The 1H NMR and
13C NMR spectra are similar to those previously reported.[18]
General Procedure for Trapping 2-Lithio-arylacetonitriles
The reactions were carried out as described for the synthesis of 8 with the
exception that the resulting reaction mixture was treated with an appropriate
trapping reagent at 08C, and the resulting solution was stirred an additional
30 min.
Physical and Spectral Properties of the Products (10)
3-Oxo-2-phenyl-butyronitrile (10d). Separated as yellowish crystalline
1
solid, mp 78–798C. H NMR (CDCl3): d 2.3 (s, 3H, 22CH3), 4.7 (s, 1H,
-CH-), 7.42–7.44 (m, 5H, aromatic). 13C NMR (CDCl3): d 27.3 (CH3) 51
(CH), 116.5 (CN), 128.3 (CH), 128.5 (CH), 128.7 (CH), 129.7 (CH), 129.8
(C), 130.0 (CH), 196.8 (C55O). Anal. calcd. for C10H9NO: C, 75.45;
H, 5.70; N, 8.80. Found: C, 75.64; H, 5.77; N, 8.91.
2-Methyl-3-oxo-2-phenyl-butyronitrile (10e). Separated as reddish gummy
1
liquid. H NMR (CDCl3): d 1.83 (s, 3H, CH3), 2.29 (s, 3H, CH3), 7.34–
7.50 (m, 5H, aromatic). 13C NMR (CDCl3): d 15.3 (CH3), 21.8 (CH3), 54.1
(c), 116.5 (CN), 128.7 (CH), 128.9 (CH), 129.5 (CH), 129.6 (CH), 129.9
(CH), 137.5 (C), 199.1 (C). Anal. calcd. for C11H11NO: C, 76.28; H, 6.40;
N, 8.09. Found: C, 76.45; H, 6.45; N, 8.15.
2-Ethyl-3-oxo-2-phenyl-butyronitrile (10f). Separated as reddish gummy
1
liquid. H NMR (CDCl3): d 0.97 (t, 3H, -CH3), 2.21–2.25 (m, 2H, -CH2-),
2.28 (s, 3H, -CH3) 7.27–7.67 (m, 5H, aromatic). 13C NMR (CDCl3): d 8.0
(CH3), 18.3 (CH3), 22.1 (CH2), 56.3 (C), 116.3 (CN), 125.3 (CH), 128.4
(CH), 139.3 (C), 199.1 (C). Anal. calcd. for C12H13NO: C, 76.98; H, 7.00;
N, 7.48. Found: C, 76.88; H, 7.15; N, 7.50.

Facile One-Pot Synthesis via Benzyne Reaction Nitriles
3503
3-Oxo-2,3-diphenylpropionitrile (10 g). Separated as colorless gummy oil.
1H NMR (CDCl3): d 5.62 (s, 1H, -CH), 7.39–7.50 (m, 7H, aromatic), 7.61
(dd, J ¼ 7.6, 7.8 Hz, 1H aromatic), 7.97 (d, J ¼ 7.9 Hz, 2 H, aromatic). 13C
NMR (CDCl3): d 47.1 (CH), 116.9 (CN), 128.7 (CH), 129.1 (CH), 129.4
(CH), 129.6 (CH), 129.8 (CH), 130.1 (CH), 130.8 (C), 134.1 (C), 134.8 (C),
189.3 (C55O). Anal. calcd. for C15H11NO: C, 81.43; H, 5.01; N, 6.33.
Found: C, 81.58; H, 5.06; N, 6.70.
2-Methyl-3-oxo-2,3-diphenyl-propionitrile (10 h). Separated as colorless
gummy oil. The 1H NMR and 13C NMR spectra are similar to those
reported previously.[19]
3-Oxo-2-phenyl-3-(3,4,5-trimethoxyphenyl)-propionitrile (10i). Separated
1
as colorless low-melting solid. H NMR (CDCl3) d 3.81 (s, 3 H, -OMe),
3.84 (s, 3 H, -OMe), 3.88 (s, 3 H, -OMe), 5.64 (s, 1 H, CH), 7.17 (s, 2H,
aromatic), 7.36–7.43 (m, 5 H, aromatic). 13C NMR (CDCl3) d 47.2 (CH),
56.7 (OMex2), 61.4 (OMe), 107.4 (CH), 117.2 (CN), 128.5 (CH), 128.8
(CH), 129.6 (CH), 103.1 (CH), 131.3 (C), 144.0 (C), 153.5 (C), 188.3
(C55O). Anal. calcd. for C19H17NO4: C, 69.44; H, 5.50; N, 4.50. Found:
C, 69.55; H, 5.58; N, 4.61.
3-Oxo-(3-thiophene-2-yl)-propionitrile (10j). Separated as reddish brown
1
gummy liquid. H NMR (CDCl3): d 5.47 (s, 1H, -CH), 7.14 (dd, J ¼ 4.5,
4.5 Hz, 1H, aromatic), 7.38–7.43 (m, 3H, aromatic), 7.50 (d, J ¼ 7.3 Hz,
2H, aromatic), 7.73 (d, J ¼ 4.5 Hz, 1H, aromatic), 7.83 (d, J ¼ 3.8 Hz, 1H,
aromatic). 13C NMR (CDCl3): d 47.9 (CH), 116.8 (CN), 128.6 (CH), 129.1
(CH), 129.6 (CH), 130.0 (CH), 130.8 (C), 134.8 (CH), 136.8 (CH), 140.5
(C), 182.0 (C). Anal. calcd. for C13H9NOS: C, 68.70; H, 3.99; N, 6.16.
Found: 68.70; H, 4.02; N, 6.20.
2-Methyl-3-oxo-2-phenyl-(thiophen-2-yl)-propionitrile (10 k). Separated
as colorless crystals, mp 65–678C (lit.[19] 65–678C).
3-(Furan-2-yl)-3-oxo-2-phenyl)-propionitrile (10l). Separated as yellowish
1
solid. Mp 85–868C (lit.[24] 89–89.58C). H NMR (CDCl3): d 5.50 (s, 1H,
-CH), 6.60 (s, 1H, aromatic), 7.39–7.41 (m, 4H, aromatic), 7.51
(d, J ¼ 7.7 Hz, 2H, aromatic), 7.66 (s, 1H, aromatic). 13C NMR (CDCl3): d
46.8 (CH), 113.8 (CH), 116.5 (CN), 120.8 (CH), 128.7 (CH), 129.5 (CH),
129.8 (CH), 130.3 (C), 148.2 (C), 177.8 (C). Anal. calcd. for C13H9NO2:
C, 73.92; H, 4.29; N, 6.63. Found: C, 73.97; H, 4.33; N, 6.70.
3-Morpholin-4-yl-3-oxo-2-phenyl)-propionitrile (10n). Separated as
1
yellowish gummy liquid. H NMR (CDCl3): d 2.90–3.04 (m, 2H, -CH2-),
3.41–3.61 (m, 2H, -CH2-), 5.67 (s, 1H, -CH-), 7.27–7.61 (m, 5H,
aromatic). 13C NMR (CDCl3): d 15.3 (CH2), 31.6 (CH2), 47.0 (CH), 117.1

3504
S. Kamila, B. Koh, and E. R. Biehl
(CN), 127.7 (CH), 128.7 (CH), 129.3 (CH), 129.6 (CH), 130.8 (CH), 134.0
(C), 189.4 (C). Anal. calcd. for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17.
Found: C, 67.90; H, 6.20; N, 12.28.
2-Methyl-3-morpholin-4-yl-3-oxo-2-phenyl)-propionitrile (10o). Separated
as colorless gummy liquid. 1H NMR (CDCl3): d 1.81 (s, 3H, CH3), 3.01–3.04
(m, 2H, -CH2-), 3.47–3.66 (m, 6H, -CH2 X3), 7.33–7.42 (m, 5H, aromatic).
13C NMR (CDCl3): d 29.5 (CH3), 44.1 (CH2), 47.3 (C), 47.6 (CH2), 65.7
(CH2), 66.8 (CH2), 120.0 (CN), 125.2 (CH), 128.9 (CH), 130.3 (CH), 138.0
(C), 164.0 (C). Anal. calcd. for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47.
Found: C, 68.99; H, 6.70; N, 11.60.
2-Morpholin-4-carbonyl-2-phenyl-pentanenitrile (10p). Separated as
1
colorless gummy liquid. H NMR (CDCl3): d 0.94 (t, 3H, -CH3), 1.97–2.4
(m, 2H, -CH2), 2.9–3.09 (m, 2H, -CH2), 3.42–3.46 (m, 4H, -CH2 X2),
7.32–7.42 (m, 5H, aromatic). 13C NMR (CDCl3): d 9.8 (-CH3), 31.4
(-CH2), 34.4 (-CH2), 44.1 (-CH2), 47.5 (-CH2), 52.9 (C), 65.7 (-CH2), 66.8
(-CH2), 119.0 (CN), 125.8 (CH), 128.8 (CH), 129.8 (CH), 136.1 (C), 164.8
(C). Anal. calcd. for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C,
70.76; H, 7.51; N, 10.42.
2-Methyl-3-oxo-2-phenyl-(3-piperidin-1-yl)-propionitrile (10q). Separated
1
as colorless gummy liquid. H NMR (CDCl3): d 0.86–0.87 (m, 2H, -CH2-),
1.39–1.49 (m, 4H, -CH2-X2), 1.81 (s, 3H, -CH3), 3.17–3.32 (m, 2H,
-CH2-), 3.55–3.63 (m, 2H, -CH2-), 7.32–7.39 (m, 5H, aromatic). 13C NMR
(CDCl3): d 24.4 (CH2), 25.0 (CH2), 25.7 (CH2), 29.8 (CH3), 45.0 (CH2),
47.3 (C), 48.1 (CH2), 120.4 (CN), 125.2 (CH), 128.6 (CH), 129.8 (CH),
138.5 (C), 164.4 (C). Anal. calcd. for C15H18N2O: C, 74.35; H, 7.49; N,
11.56. Found: C, 74.59; H, 7.60; N, 11.60.
(Z)-2-Phenyl-3-(1-H-pyrrol-2-yl)-acrylonitrile (10r). Separated as reddish
brown gummy liquid. 1H NMR (CDCl3): d 6.90 (d, J ¼ 7.8 Hz, 1H,
aromatic), 7.11 (dd, J ¼ 7.5, 7.8 Hz, 1H, aromatic), 7.20 (dd, J ¼ 7.8,
8.0 Hz, 2H, aromatic), 7.23–7.27 (m, 2H, aromatic), 7.32 (d, J ¼ 7.8 Hz,
1H, aromatic), 7.55 (s, 1H, vinylic proton), 7.62 (d, J ¼ 7.5 Hz, 1H,
aromatic), 10.1 (brs, 1H, NH). 13C NMR (CDCl3): d 108.1 (CH), 113.6 (C),
117.2 (CN), 118.9 (CH), 119.1 (C), 126.3 (CH), 126.5 (CH), 127.7 (CH),
128.5 (CH), 133.9 (C), 140 (CH). Anal. calcd. for C13H10N2: C, 80.39; H,
5.19; N, 14.42. Found: 80.44; H, 5.25; N, 14.50.
3-Hydroxy-2-phenyl-3-(thiophen-2-yl)-propionitrile (10s). Separated as
yellowish gummy liquid. 1H and 13C NMR spectra similar as that previously
1
reported. H NMR (CDCl3): d 2.02 (brs, 1H, -OH), 4.76 (d, J ¼ 6.6 Hz, 1H,
-CH), 5.4–5.5 (m, 1H, -CH-OH), 6.97 (dd, J ¼ 4.5, 4.5 Hz, 1H, aromatic),
7.23–7.38 (m, 4H, aromatic), 7.47–7.49 (m, 3H, aromatic). 13C NMR

Facile One-Pot Synthesis via Benzyne Reaction Nitriles
3505
(CDCl3): d 38.5 (CH), 77.4 (CH-OH), 116.8 (CN), 124.3 (CH), 125.3 (CH),
128.6 (CH), 129.1 (CH), 129.6 (CH), 130.6 (C), 130.8, 134.8 (CH), 136.8
(CH), 146.5 (C). Anal. calcd. for C13H11NOS: C, 68.09; H, 4.84; N, 6.11.
Found: C, 68.20; H, 4.99; N, 6.15.
3-Hydroxy-2-phenyl-3-furan-2-yl)-propionitrile (10t). Separates as
1
brownish gummy liquid. H NMR (CDCl3): d 2.25 (brs, 1H, -OH), 4.62
(d, J ¼ 6.5 Hz, 1H, -CH-), 5.1–5.6 (m, 1H, -CH-OH), 6.31 (s, 1H,
aromatic), 6.60 (s, 1H, aromatic), 7.37–7.51 (m, 5H, aromatic), 7.66 (s, 1H,
aromatic). 13C NMR (CDCl3): d 39.0 (CH), 70.34 (CH-OH), 108.6 (CH),
110.9 (CH), 116.5 (CN), 128.5 (CH), 128.7 (CH), 129.5 (CH), 129.8 (CH),
130.6 (C), 142.9 (CH), 158.5 (C). Anal. calcd. for C13H11NO2: C, 73.23;
H, 5.20; N, 6.57. Found: C, 7.40; H, 5.25; N, 6.70.
ACKNOWLEDGMENT
We thank the Robert Welch Foundation, Houston, Texas, for generous
financial support of this work.
REFERENCES
1. (a) Heller, B.; Sundermann, B.; Buschmann, H.; Drexler, H. J.; You, J.;
Holzgrabe, U.; Heller, E.; Oehme, G. Photocatyzed [2 þ 2 þ 2] cycloaddition of
nitriles with acetylene: An effective method for the synthesis of 2-pyridines under
mild conditions. J. Org. Chem. 2002, 67, 4414–4422; (b) Leader, H.;
Smejkal, R. M.; Payne, C. S.; Padilla, F. N.; Doctor, B. P.; Gordon, R. K.;
Chiang, P. K. Binary antidotes for organophosphate poisoning: Aprophen analogs
that are both antimuscarinics and carbamates. J. Med. Chem. 1989, 32,
1522–1528; (c) Trivedi, B. K.; Holmes, A.; Stoeber, T. L.; Blankey, C. J.;
Roark, W. H.; Picard, J. A.; Shaw, M. K.; Essenburg, A. D.; Stanfield, R. L.;
Krause, B. R. Inhibitors of acyl-CoA: Chlolesterol acyltransferase, 4: A novel
series of urea ACAT inhibitors as potential hypocholestereolemic agents. J. Med.
Chem. 1993, 36, 3300–3307; (d) Convery, M. A.; Davis, A. P.; Dunne, C. J.;
Mackinnon, J. W. Synthesis and properties of enantiopure bicyclic amidines. Tetra-
hedron Lett. 1995, 36, 4279–4282; (e) Tiecco, M.; Testaferri, L.; Tingoli, M.;
Bartoli, D. Iodine (III)–mediated acetoxy-lactonization of unsaturated nitriles. Tet-
rahedron 1990, 46, 7139–7150; (f) Pascal, C.; Dubois, J.; Guenard, D.;
Tchertanor, L.; Thoret, S.; Gueritte, F. Antimitotic agents interacting with tubulin:
Synthesis and structure–activity relationships of novel ortho bridged biphenyls of
the rhazinilam type. Tetrahedron 1998, 54, 14737–14756.
2. Dei, S.; Romanelli, M. N.; Scapecchi, S.; Teodori, E.; Chiarini, A.; Gualtieri, F.
Verapamil analog with restricted molecular flexibility. J. Med. Chem. 1991, 34,
2219–2225.
3. Hartmann, R. W.; Batzl, C. Aromatase inhibitors. Synthesis and evaluation of
mammary tumor inhibiting activity of 3-alkylated 3-(4-aminophenyl)-piperidine-
2,6-diones. J. Med. Chem. 1986, 29, 1362–1369.

3506
S. Kamila, B. Koh, and E. R. Biehl
4. For reviews, see Harvey, H. A.; Lipton, A.; Santen, R. J. Cancer Res. 1982,
42 (Suppl.), 3261–3469.
5. Santen, R. J.; Samojlik, E.; Worgul, T. J. A Comprehensive Guide to the Thera-
peutic Use of Aminoglutethimide; Santen, R. J., Henderson, I. C. Eds.; Karger:
Basel 1982, p. 101.
6. Harris, A. L.; Powles, T. J.; Smith, I. E.; Coombes, R. C.; Ford, H. T.; Gazet, J. C.;
Harmer, C. L.; Morgan, M.; White, H.; Parsons, C. A.; McKinna, J. A. Aminoglu-
tethimide for the treatment of advanced postmenopausal breast cancer. Eur. J.
Cancer Clin. Oncol. 1983, 19, 11.
7. Henderson, I. C.; Canellos, G. P. N. Engl. J. Med. 1980, 302 (17), 78.
8. Santen, R. J.; Worgul, T. J.; Samojlik, E.; Interrante, A.; Zoucher, A. E.;
Lipton, A.; Harvey, H. A.; White, D. S.; Smart, E.; Cox, C.; Wells, S. A. A ran-
domized trial comparing surgical adrenalectomy with aminoglutethimide plus
hydrocortisone in women with advanced breast cancer. N. Engl. J. Med. 1981,
30, 545.
9. (a) Kelp, S. S.; McGee, M. J. Oxidative declamation of benzyl and benzhydryl
cyanides: A simplified procedure. J. Org. Chem. 1983, 48, 4097–4098;
(b) Im, D. S.; Cheong, C. S.; Lee, S. H.; Youn, B. H.; Kim, S. C. Chemoenzymatic
synthesis of optically active 2-phenyl-2-(1H-1,2,4-triazol-1-ylmethyl)hexaneni-
trile. Tetrahedron 2000, 56, 1309; (c) Wu, Z. L.; Li, Z. Y. Enantioselective
hydrolysis of various racemic a-substituted arylacetonitriles using Rhodococcus
sp. Tetrahedron Asymmetry 2001, 12, 3305–3312; (d) Takaya, H.; Yoshida, K.;
Isozaki, K.; Terai, H.; Murahashi, S. I. Angew. Chem.; Int. Ed. 2003, 42, 3302.
10. See Biehl, E.; Khanapure, S. Application of the aryne reaction in the synthesis of
polycyclics. Acc. Chem. Res. 1989, 22, 275, and references therein.
11. Biehl, E. R.; Smith, S. M.; Lapis, S.; Reeves, P. C. Investigation of the mechanism
of reductive dehalogenation of haloanisoles under aryne-forming conditions.
J. Org. Chem. 1972, 37, 3529–3530.
12. See Sathunuru, R.; Zhang, H.; Rees, C. W.; Biehl, E. R. Facile synthesis of 2-sub-
stituted 4H-1,3-thiazines and 3-substituted 1,2-isothiazoles using benzyne inter-
mediates. Heterocycles 2005, 64, 579, and references therein.
13. Kitamura, T.; Yamane, M.; Inoue, K.; Todak, M.; Fukatsu, N.; Meng, Z.;
Fujiwara, Y. A new and efficient hypervalent iodine–benzyne precursor,
(phenyl][o-(trimethylsilyl)phenyl]iodonium triflate: Generation, trapping
reaction, and nature of benzyne. J. Am. Chem. Soc. 1999, 121, 11674–11679.
14. Motokura, K.; Nishimura, D.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. A
ruthenium-grafted hydrotalcite as a multifunctional catalyst for direct a-alkylation
of nitriles with primary alcohols. J. Am. Chem. Soc. 2004, 126, 5662–5663.
15. Im, D. S.; Cheong, C. S.; Lee, S. H.; Youn, B. H.; Kim, B. H. Chemoenzymatic
synthesis of optically active 2-phenyl-2-(1H-1,2,4-triazol-1-ylmethyl)-hexanane-
nitrile. Tetrahedron 2000, 56, 1309–1314.
16. Gao, C.; Tao, X.; Qian, Y.; Huang, J. A convenient and efficient palladium-
catalyzed system for cross coupling of aryl bromides with active methylene
compounds. Synlett 2003, 1716–1718.
17. Khanapure, S. P.; Crenshaw, L.; Reddy, R. T.; Biehl, E. R. Synthesis of polysub-
stituted benzenes via the tandem addition–rearrangement aryne reaction of substi-
tuted 2-bromoanisoles and lithionitrile. J. Org. Chem. 1988, 53, 4915–4921.
18. Kobayashi, K.; Uneda, T.; Takada, K.; Tanaka, H.; Kitamura, T.; Morikawa, O.;
Konishi, H. Efficient synthesis of 1-amino-2-naphthalenecarboxylic acid deriva-
tives via a sequential Michael addition/enolate-nitrile coupling route and its

Facile One-Pot Synthesis via Benzyne Reaction Nitriles
3507
application to facile preparation of 9-amino analogs of arylnaphthofuranone
lignans. J. Org. Chem. 1997, 62, 664–668.
19. Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. Expedient acylations of
primary and secondary alkyl cyanides to a-substituted a-ketonitriles. J. Org.
Chem. 2003, 68, 4932–4934.
20. Compton, D. R.; Carlson, K. E. I. Y.; Katzenellenbogen, B. S. Pyrazolo-[1,5-a]pyr-
imidines as estrogen receptor ligands: Defining the orientation of a novel hetero-
cyclic core. Bioorg. Med. Chem. Lett. 2004, 14, 5681–5684.
21. Compton, D. R.; Sheng, S.; Carlson, K. E.; Rebacz, N. A.; Lee, I. Y.;
Katzenellenbogen, B. S. J. Med. Chem. 2004, 47, 5872–5893.
22. See, for example, Kayaleh, N. E.; Gupta, R. C.; Johnson, F. Enolates ions as 3-acti-
vators of otho-metalation: Direct synthesis of 3-aminoindenones. J. Org. Chem.
2000, 65, 4515–4522.
23. Pansegrau, P. D.; Ricker, W. F.; Meyers, A. I. The oxazoline–benzyne route to
1,2,3-trisubstituted benzenes: Tandem addition of organolithiums, organocuprates,
and a-lithionitriles to benzynes. J. Am. Chem. Soc. 1988, 110, 7178–7184.
24. Tripathy, S.; Hussian, H.; Durst, T. Iodine ate complexes and N-lithiobenzocyclo-
butenamine intermediates in the reaction of a-lithionitriles with benzyne. Tetra-
hedron Lett. 2000, 41, 8401–8405.
25. Beak, P.; Meyers, A. I. Stereo- and regiocontrol by complex induced proximity
effects: Reactions of organolithium compounds. Acc. Chem. Res. 1986, 19, 356.
26. Freerksen, R. W.; Selikson, S. J.; Wroble, R. R. Oxidative decyanation of
secondary nitriles to ketones. J. Org. Chem. 1983, 48, 4087–4096.
27. Takagi, S.; Yasuda, H.; Kono, M. Syntheses of 4,5-disubstituted isoxazoles and
their cleavage reaction with sodium ethoxide, V: Reaction of isozazole and a
a-cyano ketone possessing a furan ring. Yakugaku Zasshi 1961, 81, 1559–1563;
Chem. Abstr. 1962, 57, 83200.