Cyanide anion as a leaving group in nucleophilic aromatic substitution: Synthesis of quaternary centers at azine heterocycles

Article abstract of DOI:10.1021/jo302307y

Nucleophilic aromatic substitution of 2- or 4-cyanoazines with the anions derived from aliphatic α,α-disubstituted esters and nitriles leads to displacement of the cyanide function. Enabling cyanides to be used as highly active leaving groups in S_NAr reactions provides additional flexibility in starting materials for synthesis. We show that, in many cases, the cyanide leaving group is displaced preferentially in the presence of halogens. The resulting heteroaryl iodides, bromides, and chlorides subsequently can be used as handles for further chemical diversification.

Full text of DOI:10.1021/jo302307y

Note
pubs.acs.org/joc
Cyanide Anion as a Leaving Group in Nucleophilic Aromatic
Substitution: Synthesis of Quaternary Centers at Azine Heterocycles
Alexander D. Thompson and Malcolm P. Huestis*
Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
S
* Supporting Information
ABSTRACT: Nucleophilic aromatic substitution of 2- or 4-cyanoazines with the anions
derived from aliphatic α,α-disubstituted esters and nitriles leads to displacement of the
cyanide function. Enabling cyanides to be used as highly active leaving groups in SNAr
reactions provides additional flexibility in starting materials for synthesis. We show that,
in many cases, the cyanide leaving group is displaced preferentially in the presence of
halogens. The resulting heteroaryl iodides, bromides, and chlorides subsequently can be
used as handles for further chemical diversification.
noted unintentional displacement of a nitrile functional group
he classical method of forging aliphatic carbon−carbon
Tbonds to arenes by electrophilic aromatic substitution on the pyridine electrophile.5 Herein, we report further studies
on the use of the cyanide leaving group in forming quaternary
centers via SNAr chemistry.7−11
(SEAr) onto alkyl halides continues to be of general use over
130 years after its discovery by Friedel and Crafts.1 While
nucleophilic aromatic substitution (SNAr) has been used
extensively to secure aryl linkages to heteroatoms,2 studies
describing the use of SNAr to furnish carbon−carbon bonds
without using stabilized carbanions derived from malonates
have only been reported recently.3−5
In 2005, Klapars and Waldman at Merck identified the first
highly effective aliphatic α-nitrile arylation, spanning a broad
spectrum of heteroaryl halide acceptors.3a Previously, quater-
nary motifs of this type were accessed by palladium-catalyzed
reactions of enolates with aryl halides, a reaction type with very
few heteroaromatic examples (Figure 1).6 Shortly after this
initial publication, another Merck group demonstrated that
heteroaryl halogen electrophiles could also be intercepted by
ester enolates under similar conditions.4 In 2009, during a
medicinal chemistry campaign that utilized the Klapars and
Waldman α-nitrile arylation method, a third Merck group
We now show that SNAr reaction of the potassium and
lithium anions derived from aliphatic α,α-disubstituted esters
and nitriles with 2- or 4-cyanoazines leads to products with
overall ipso substitution of the carbonitrile. In nearly all cases,
reaction pathways such as addition to the arylnitrile carbon or
competing displacement of halide functional groups do not
occur. Aryl halides are by far the most commonly used leaving
groups for SNAr chemistry and are critical handles for late-stage
molecular diversification of arenes. Thus, halide-sparing
transformations such as the reaction presented here constitute
valuable additions to the synthetic chemist’s toolbox.
As depicted in Table 1, quaternary azine α-nitriles can be
obtained in good yield by this operationally simple method.
This type of motif has recently seen utility in drug discovery
settings12 for which there existed no practical synthetic
approach before the work by Merck.3a,5 In a typical example,
an equimolar quantity of cyanoazine and aliphatic nitrile in
tetrahydrofuran at −78 °C is treated with 1.1 equiv of lithium
bis(trimethylsilyl)amide and allowed to warm to room
temperature. Our work demonstrates the use of both acyclic
α,α-disubstituted nitriles as well as cyclic nitriles with 3- to 7-
membered rings. For example, isonicotinonitrile reacts in high
yield with cyclohexane carbonitrile (entry 1, 71%), tert-butyl 3-
cyanoazetidine-N-carboxylate (entry 2, 78%), and tetrahydro-
pyran carbonitrile (entry 4, 94%). For other halogen-containing
isonicotinonitrile electrophiles, we were able to include
chlorides at C2 (entry 9, 80% on gram-scale), C3 (entry 7,
82%), and C3/C5 (entry 3, 47%), as well as C3 bromides
(entry 5, 71%) and iodides (entries 6 and 8, 75% and 60%,
respectively). Surprisingly, α-lithiated aliphatic nitriles with a
heteroatom on the β-carbon do not appear to undergo
Figure 1. Literature precedent for the formation of quaternary bonds
to arenes.
Received: October 24, 2012
Published: December 13, 2012
© 2012 American Chemical Society
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Note
a
Table 1. SNAr Reaction Scope of Aliphatic α,α-Disubstituted Nitriles with Cyanoazines
a
Conditions: The azine (1 mmol) and cyanide (1 mmol) were weighed into a vial, capped with a septum, and purged with nitrogen gas. Anhydrous
THF (5 mL) was added, and the mixture was cooled to −78 °C while stirring. LiHMDS (1.1 mL, 1.0 M in THF) was added before removal of the
b
c
cooling bath and the reaction mixture allowed to warm to room temperature. 1.4 equiv of LiHMDS. Gram scale (4.5 mmol).
spontaneous ring-opening to any appreciable extent (entries 2,
6, and 7). For reactions of picolinonitriles, which are generally
less reactive than the isonicotinonitriles, compound 1j is
obtained in 62% yield (entry 10) and volatile fragment 1l in
39% yield (entry 12). We also were able to preserve a chloride
at C6, as exemplified by cyclobutane 1k (entry 11, 45%).
Isoquinoline 1-carbonitrile is a highly reactive electrophile,13
whereby compound 1m is obtained in almost quantitative yield
(entry 13, 97%) and we were able to obtain cyclopropane 1n
(entry 14, 37%) despite cyclopropyl carbonitrile displaying only
trace reactivity with 2- and 4-cyanopyridines.14
In the above reactions, small amounts of product resulting
from competitive halide displacement or direct attack on the
arylnitrile carbon15 were detected by HPLC−MS but were not
isolated.16 However, these byproducts do not make up the mass
balance difference for entries in which the yield was moderate.
Instead, we noticed that lower yields often result from
decomposition of products and reactants, potentially due to
extraneous base, as previously observed in the SNAr studies by
Klapars and Waldman.3a Therefore, extended reaction times
should be avoided whenever possible; typically, the reaction is
complete within 3 h.
In extending the current transformation to nucleophilic
additions of aliphatic esters, only trace reactivity was observed
with lithium bis(trimethylsilyl)amide. After screening several
additives,17 we discovered that simply switching to sodium or
potassium bis(trimethylsilyl)amide provided higher conversions
to product, with the highest levels being reached with
potassium bis(trimethylsilyl)amide. Futhermore, we did not
isolate or detect any products from competitive Claisen
condensation onto the product ester.
Thus, reaction of isonicotinonitrile with ethyl cyclobutane-
carboxylate provides volatile compound 2a in 60% yield (Table
2, entry 1). Isonicotinonitrile also reacts with a cyclic alkenyl
methyl ester to afford compound 2c (entry 3, 57%). Pyridyl
halides are retained, providing moderate yields of cyano-
selective substitution products in reactions with cyclic lactones
(entry 2, 36%), benzyl carbamate-protected piperidines (entry
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Note
a
Table 2. SNAr Reaction Scope of Aliphatic α,α-Disubstituted Esters with Cyanoazines
a
Conditions: The azine (1 mmol) and cyanide (1 mmol) were weighed into a vial, capped with a septum, and purged with nitrogen gas. Anhydrous
THF (2.5 mL) was added, and the mixture was cooled to −78 °C while stirring. KHMDS (2.2 mL, 0.5 M in toluene) was added before removal of
b
the cooling bath and the reaction mixture allowed to warm to room temperature. 1.4 equiv of LiHMDS.
4, 28%), tert-butyl carbamate protected azetidines (entry 5,
39%), and most notably, a [3.1.0]azabicyclic cyclopropane
ester, affording 2f as a single diastereomer (entry 6, 44%). The
chloro substituent also remains intact following substitution of
6-chloropicolinonitrile with ethyl N-benzylpyrrolidine-3-carbox-
ylate (entry 7, 54%).18 The isoquinoline 1-carbonitrile system is
receptive to nucleophilic attack from methyl isobutyrate (entry
8, 55%), α-methyl-γ-butyrolactone (entry 9, 94%), and a tert-
butyl carboxylate derived from norbornene, affording bicycle 2j
as a single diastereomer (entry 10, 40%). We were additionally
able to apply our method to pyrimidine-4-carbonitrile (entry
11, 62%), implying the possibility of extending cyano-SNAr
chemistry to diazines and other heteroaromatic scaffolds.19
The synthetic utility of aromatic iodides and bromides for
molecular diversification is well recognized (transition-metal-
catalyzed cross couplings, lithium−halogen exchange, etc.).
Therefore, the ability to preserve halides during our cyano-
selective SNAr reaction has great value. Recently, there has been
a surge in research toward highly active metal catalysts that
operate on less reactive arene functions such as chlorides. We
highlight some of these types of Pd(0)-catalyzed cross-
couplings in Scheme 1. Using the conditions of Dreher and
Molander, compound 1i undergoes smooth B-alkyl Suzuki
coupling with potassium cyclopropyltrifluoroborate to provide
3a in 94% yield.20 Biaryl carbon−carbon bond formation is also
achieved with 2-aminopyrimidine-5-boronic acid pinacol ester
under the conditions of Guram (3b, 56%).21 In terms of
carbon−nitrogen bond formation, 2-aminopyridine participates
in a Buchwald−Hartwig reaction under the conditions of Yin to
afford bis-2-pyridylamine 3c in 93% yield.22 Finally, the recently
reported conditions of Beller, which did not comment on the
use of secondary alcohols, were successfully employed in
engaging 2-propanol to secure a carbon−oxygen linkage (3d,
56%).23,24
As demonstrated here, azine carbonitriles undergo nucleo-
philic aromatic substitution with carbon-based enolates with net
loss of the cyano functional group. Current limitations include
the incompatibility of unsubstituted and α-monosubstituted
nitriles and esters such as acetonitrile, propionitrile, tert-butyl
propionate, and diethyl malonate. Under the current
conditions, α,α-disubstituted amides and phosphonates also
did not afford SNAr product.25 Further work may seek to
address these issues as well as expanding the range of
nucleophilic acceptors to other unsaturated heterocyclic
cyanides.
EXPERIMENTAL SECTION
■
General Procedure for SNAr Reactions A (Table 1).
WARNING: We did not discount the possibility that toxic hydrogen
cyanide gas may be formed either under the reaction conditions or
upon workup. As this could lead to a potentially fatal outcome, we
advise that extreme caution be used, especially if the reaction is
conducted on larger scale.
The azine (1 equiv) and, if solid, nitrile (1 equiv) were weighed into
a vial and purged with nitrogen gas. Anhydrous THF (5 mL) was
added, and the mixture was cooled to −78 °C (dry ice, acetone) with
stirring. If the nitrile was a liquid, it was added at this point. Lithium
bis(trimethylsilyl)amide (1.1 equiv, 1.0 M in THF [untitrated]) was
added before removal of the cooling bath and the reaction mixture
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Note
4-(Pyridin-4-yl)tetrahydro-2H-pyran-4-carbonitrile (1d). Proce-
dure A: Tetrahydro-2H-pyran-4-carbonitrile (333 mg, 3.00 mmol)
and isonicotinonitrile (312 mg, 3.00 mmol) were reacted with
LiHMDS (3.3 mL) for 2.5 h. After workup, the compound was pure,
affording 1d as a off-white solid (533 mg, 94%): Rf = 0.29 (CH2Cl2/
Scheme 1. Pd(0)-Catalyzed C−C, C−N, and C−O
Functionalization of a Chloroazine
1
MeOH, 95:5); H NMR (500 MHz, CDCl3) δ 8.70−8.66 (m, 2H),
7.45−7.40 (m, 2H), 4.15−4.08 (m, 2H), 3.94−3.87 (m, 2H), 2.18−
2.09 (m, 2H), 2.06−2.00 (m, 2H); 13C NMR (126 MHz, CDCl3) δ
150.8, 148.4, 120.6, 120.5, 64.7, 41.9, 36.0; HRMS m/z calcd for
C11H12N2O [M + H]+ 189.1022, found 189.1023.
2-(3-Bromopyridin-4-yl)-2-methylbutanenitrile (1e). Procedure A:
2-Methylbutanenitrile (83 mg, 1.00 mmol) and 3-bromoisonicotinoni-
trile (183 mg, 1.00 mmol) were reacted with LiHMDS (1.1 mL) for 3
h. Flash chromatography (heptanes/EtOAc 100:0−80:20) afforded 1e
1
as a clear oil (169 mg, 71%): Rf = 0.23(heptanes/EtOAc 80:20); H
NMR (500 MHz, CDCl3) δ 8.77 (s, 1H), 8.56 (d, J = 5.5 Hz, 1H),
7.53 (d, J = 5.5 Hz, 1H), 2.57−2.43 (m, 1H), 2.14−2.03 (m, 1H), 1.90
(s, 3H), 1.01 (t, J = 7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
154.6, 149.0, 145.6, 123.7, 121.5, 119.6, 44.2, 30.9, 24.1, 9.8; HRMS
m/z calcd for C10H11N2Br [M + H]+ 239.0178, found 239.0173.
tert-Butyl 3-cyano-3-(3-iodopyridin-4-yl)pyrrolidine-1-carboxy-
late (1f). Procedure A: tert-Butyl 3-cyanopyrrolidine-1-carboxylate
(196 mg, 1.00 mmol) and 3-iodoisonicotinonitrile (230 mg, 1.00
mmol) were reacted with LiHMDS (1.4 mL, 1.4 equiv) for 1.5 h. Flash
chromatography (CH2Cl2/MeOH 100:0−95:5) afforded 1f as a brown
1
solid (132 mg, 75%): Rf = 0.28 (CH2Cl2/MeOH, 95:5); H NMR
(500 MHz, CDCl3) δ 9.10 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 7.25 (d, J
= 5.2 Hz, 1H), 4.56−4.42 (m, 1H), 3.85 (m, 1H), 3.77−3.51 (m, 2H),
2.89−2.82 (m, 1H), 2.70−2.61 (m, 1H), 1.49 (s, 9H); 13C NMR (126
MHz, CDCl3, 335 K) δ 160.8, 153.8, 149.7, 145.5, 122.5, 118.8, 96.0,
80.8, 54.3, 43.9, 36.2, 35.6, 28.5; HRMS m/z calcd for C15H18N3O2I
[M + H]+ 400.0516, found 400.0497.
1-Benzhydryl-3-(3-chloropyridin-4-yl)azetidine-3-carbonitrile
(1g). Procedure A: 1-Benzhydrylazetidine-3-carbonitrile (248 mg, 1.00
mmol) and 3-chloroisonicotinonitrile (139 mg, 1.00 mmol) were
reacted with LiHMDS (1.1 mL) for 2.5 h. Flash chromatography
(heptanes/EtOAc 100:0−60:40) afforded 1g as a white solid (296 mg,
82%): Rf = 0.26 (heptanes/EtOAc 70:30); 1H NMR (500 MHz,
CDCl3) δ 8.61 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 7.45−7.41 (m, 4H),
7.34−7.26 (m, 4H), 7.24−7.19 (m, 2H), 7.07 (d, J = 5.0 Hz, 1H), 4.33
(s, 1H), 4.07−4.02 (m, 2H), 3.44−3.39 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 150.6, 148.6, 142.8, 140.5, 131.1, 128.9, 127.8, 127.3,
122.1, 120.2, 77.5, 61.9, 34.5; HRMS m/z calcd for C22H18N3Cl [M +
H]+ 360.1262, found 360.1270.
allowed to warm to rt. After completion as determined by TLC or
UPLC analysis, the mixture was quenched with satd aq NH4Cl and
diluted with CH2Cl2, and the layers were partitioned. The aqueous
layer was extracted with CH2Cl2 (2×), and the organic phases were
combined, dried (MgSO4), and concentrated to dryness. The resulting
residue was purified by flash chromatography using the stated eluent
system.
1-(Pyridin-4-yl)cyclohexanecarbonitrile (1a). Procedure A: cyclo-
hexanecarbonitrile (109 mg, 1.00 mmol) and isonicotinonitrile (104
mg, 1.00 mmol) were reacted with LiHMDS (1.4 mL, 1.4 equiv) for
1.5 h. Flash chromatography (CH2Cl2/MeOH 100:0−95:5) afforded
1a as a white solid (132 mg, 71%); Rf = 0.29 (CH2Cl2/MeOH, 95:5);
1H NMR (500 MHz, CDCl3) δ 8.65−8.61 (m, 2H), 7.45−7.39 (m,
1-(3-Iodopyridin-4-yl)cyclohex-3-enecarbonitrile (1h). Procedure
A: Cyclohex-3-enecarbonitrile (107 mg, 1.00 mmol) and 3-
iodoisonicotinonitrile (230 mg, 1.00 mmol) were reacted with
LiHMDS (1.1 mL) for 4 h. Flash chromatography (heptanes/EtOAc
100:0−70:30) afforded 1h as a white solid (187 mg, 60%): Rf = 0.25
2H), 2.17−2.10 (m, 2H), 1.92−1.72 (m, 7H), 1.36−1.24 (m, 1H); 13
C
NMR (126 MHz, CDCl3) δ 150.5, 150.1, 121.4, 120.7, 44.3, 36.7, 24.8,
23.3; HRMS m/z calcd for C12H14N2 [M + H]+ 187.1230, found
187.1218.
1
(heptanes/EtOAc 70:30); H NMR (500 MHz, CDCl3) δ 9.08 (s,
1H), 8.55 (d, J = 5.4 Hz, 1H), 7.37 (d, J = 5.4 Hz, 1H), 5.89 (d, J =
10.0 Hz, 1H), 5.78 (d, J = 10.0 Hz, 1H), 3.11 (d, J = 17.3 Hz, 1H),
2.66 (d, J = 17.3 Hz, 1H), 2.56−2.45 (m, 2H), 2.40−2.27 (m, 1H),
2.21−2.05 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 161.0, 149.6,
147.9, 127.5, 122.8, 122.3, 119.9, 95.3, 42.1, 34.0, 29.9, 22.8; HRMS
m/z calcd for C12H11N2I [M + H]+ 311.0040, found 311.0075.
tert-Butyl 4-(2-Chloropyridin-4-yl)-4-cyanoazepane-1-carboxy-
late (1i). Procedure A: tert-Butyl 4-cyanoazepane-1-carboxylate (1.00
g, 4.45 mmol) and 2-chloroisonicotinonitrile (618 mg, 4.45 mmol)
were reacted with LiHMDS (4.9 mL) for 2 h. Flash chromatography
(heptanes/EtOAc 100:0−70:30) afforded 1i as a clear viscous oil (1.20
tert-Butyl 3-Cyano-3-(pyridin-4-yl)azetidine-1-carboxylate (1b).
Procedure A: tert-Butyl 3-cyanoazetidine-1-carboxylate (182 mg, 1.00
mmol) and isonicotinonitrile (104 mg, 1.00 mmol) were reacted with
LiHMDS (1.1 mL) for 1.5 h. Flash chromatography (CH2Cl2/MeOH
100:0−95:5) afforded 1b as a white solid (203 mg, 78%): Rf = 0.24
1
(CH2Cl2/MeOH 95:5); H NMR (500 MHz, CDCl3) δ 8.75−8.71
(m, 2H), 7.55−7.50 (m, 2H), 4.65 (d, J = 8.8 Hz, 2H), 4.21 (d, J = 8.8
Hz, 2H), 1.50 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 155.4, 151.0,
145.4, 120.2, 119.3, 81.5, 60.8 (br), 33.9, 28.3; HRMS m/z calcd for
C14H17N3O2 [M + H]+ 260.1394, found 260.1399.
2-(3,5-Dichloropyridin-4-yl)-2-methylpropanenitrile (1c). Proce-
dure A: isobutyronitrile (69 mg, 1.00 mmol) and 3,5-dichloroisoni-
cotinonitrile (173 mg, 1.00 mmol) were reacted with LiHMDS (1.1
mL) for 1.5 h. Flash chromatography (heptanes/EtOAc 100:0−80:20)
afforded 1c as a white solid (101 mg, 47%): Rf = 0.38 (Heptanes/
1
g, 80%); Rf = 0.23 (heptanes/EtOAc 70:30); H NMR (500 MHz,
CDCl3, 335 K) δ 8.41 (d, J = 5.3 Hz, 1H), 7.42 (d, J = 1.7 Hz, 1H),
7.30 (dd, J = 5.3, 1.7 Hz, 1H), 4.15−3.77 (m, 1H), 3.77−3.61 (m,
1H), 3.51−3.20 (m, 2H), 2.20−1.93 (m, 6H), 1.49 (s, 9H); 13C NMR
(126 MHz, CDCl3, 335 K) δ 155.4 (br), 153.6, 152.8, 150.6, 121.1,
120.1, 119.2, 80.3, 46.9, 45.3 (br), 42.9, 41.0 (br), 36.9 (br), 28.6, 24.5;
HRMS m/z calcd for C17H22N3O2Cl [M + H]+ 336.1473, found
336.1461.
1
EtOAc 80:20); H NMR (500 MHz, CDCl3) δ 8.50 (s, 2H), 2.08 (s,
6H); 13C NMR (126 MHz, CDCl3) δ 150.5, 141.6, 131.3, 122.6, 38.3,
28.4; HRMS m/z calcd for C9H8N2Cl2 [M + H]+ 215.0137, found
215.0165.
765
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Note
4-(Pyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (1j). Procedure
A: Tetrahydro-2H-pyran-4-carbonitrile (111 mg, 1.00 mmol) and
picolinonitrile (104 mg, 1.00 mmol) were reacted with LiHMDS (1.1
mL) for 2 h. Flash chromatography (CH2Cl2/MeOH 100:0−95:5)
afforded 1j as a white solid (116 mg, 62%): Rf = 0.50 (CH2Cl2/MeOH
95:5); 1H NMR (500 MHz, CDCl3) δ 8.65−8.61 (m, 1H), 7.80−7.74
(m, 1H), 7.61−7.57 (m, 1H), 7.32−7.25 (m, 1H), 4.12−4.06 (m, 2H),
3.94−3.85 (m, 2H), 2.41−2.33 (m, 2H), 2.08−2.02 (m, 2H); 13C
NMR (126 MHz, CDCl3) δ 157.9, 149.7, 137.4, 123.2, 121.6, 120.4,
64.8, 44.1, 35.2; HRMS m/z calcd for C11H12N2O [M + H]+ 189.1022,
found 189.1012.
1-(6-Chloropyridin-2-yl)cyclobutanecarbonitrile (1k). Procedure
A: cyclobutanecarbonitrile (81 mg, 1.00 mmol) and 6-chloropicolino-
nitrile (138 mg, 1.00 mmol) were reacted with LiHMDS (1.1 mL) for
3 h. Flash chromatography (heptanes/EtOAc 100:0−80:20) afforded
1k as a clear oil (86 mg, 45%): Rf = 0.47 (Heptanes/EtOAc 80:20); 1H
NMR (500 MHz, CDCl3) δ 7.71−7.66 (m, 1H), 7.47 (d, J = 7.9 Hz,
1H), 7.29 (d, J = 7.9 Hz, 1H), 2.95−2.86 (m, 2H), 2.77−2.68 (m,
2H), 2.46−2.35 (m, 1H), 2.21−2.12 (m, 1H); 13C NMR (126 MHz,
CDCl3) δ 158.2, 151.5, 139.6, 123.6, 123.3, 119.1, 41.7, 33.7, 16.9;
HRMS m/z calcd for C10H9N2Cl [M + H]+ 193.0527, found 193.0520.
2-Methyl-2-(pyridin-2-yl)propanenitrile (1l). Procedure A: Isobu-
tyronitrile (69 mg, 1.00 mmol) and picolinonitrile (104 mg, 1.00
mmol) were reacted with LiHMDS (1.1 mL) for 3 h. Flash
chromatography (heptanes/EtOAc 100:0−70:30) afforded 1l as a
colorless liquid (57 mg, 39%): Rf = 0.47 (heptanes/EtOAc 70:30); 1H
NMR (500 MHz, CDCl3) δ 8.61 (d, J = 5.2 Hz, 1H), 7.77−7.71 (m,
1H), 7.59 (d, J = 7.6 Hz, 1H), 7.26−7.23 (m, 1H), 1.77 (s, 6H); 13C
NMR (126 MHz, CDCl3) δ 159.5, 149.5, 137.2, 124.3, 122.8, 119.8,
39.5, 27.8; HRMS m/z calcd for C9H10N2 [M + H]+ 147.0917, found
147.0931.
trile (104 mg, 1.00 mmol) were reacted with KHMDS (2.2 mL) for 1
h. Flash chromatography (CH2Cl2/MeOH, 100:0−95:5) afforded 2a
as an orange oil (125 mg, 60%): Rf = 0.30 (CH2Cl2/MeOH, 95:5); 1H
NMR (500 MHz, CDCl3) δ 8.57−8.54 (m, 2H), 7.24−7.20 (m, 2H),
4.12 (q, J = 7.0 Hz, 2H), 2.88−2.81 (m, 2H), 2.52−2.44 (m, 2H),
2.14−2.04 (m, 1H), 1.95−1.83 (m, 1H), 1.18 (t, J = 7.0 Hz, 3H).; 13
C
NMR (126 MHz, CDCl3) δ 174.5, 152.5, 149.8, 121.5, 61.3, 51.9, 32.0,
16.7, 14.0; HRMS m/z calcd for C12H15NO2 [M + H]+ 206.1176,
found 206.1176.
Note: This compound was somewhat volatile under high vacuum.
3-(2,6-Dichloropyridin-4-yl)-3-methyldihydrofuran-2(3H)-one
(2b). Procedure B: 3-Methyldihydrofuran-2(3H)-one (128 mg, 1.00
mmol) and 2,6-dichloroisonicotinonitrile (173 mg, 1.00 mmol) were
reacted with KHMDS (2.2 mL) for 2.5 h. Flash chromatography
(heptanes/EtOAc 100:0−70:30) afforded 2b as a white solid (88 mg,
36%); Rf = 0.28 (heptanes/EtOAc 70:30); 1H NMR (500 MHz,
CDCl3) δ 7.39 (s, 2H) 4.44−4.39 (m, 1H), 4.33−4.28 (m, 1H), 2.70−
2.64 (m, 1H), 2.52−2.45 (m, 1H), 1.63 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 177.4, 156.1, 151.3, 120.7, 65.0, 46.8, 36.6, 25.0; HRMS m/z
calcd for C10H9NO2Cl2 [M + Na]+ 267.9903, found 267.9923.
Methyl 1-(Pyridin-4-yl)cyclopent-3-enecarboxylate (2c). Proce-
dure B: Methyl cyclopent-3-enecarboxylate (126 mg, 1.00 mmol) and
isonicotinonitrile (104 mg, 1.00 mmol) were reacted with KHMDS
(2.2 mL) for 2 h. Flash chromatography (CH2Cl2/MeOH 100:0−
90:10) afforded 2c as an orange solid (115 mg, 57%): Rf = 0.51
1
(CH2Cl2/MeOH 90:10); H NMR (500 MHz, CDCl3) δ 8.60−8.46
(m, 2H), 7.25−7.16 (m, 2H), 5.80−5.70 (m, 2H), 3.67 (s, 3H), 3.42−
3.31 (d, J = 17.8 Hz, 2H), 2.74 (d, J = 17.8 Hz, 2H); 13C NMR (126
MHz, CDCl3) δ 175.2, 152.6, 149.9, 128.8, 121.6, 57.7, 52.8, 42.6;
HRMS m/z calcd for C12H13NO2 [M + H]+ 204.1019, found
204.1045.
Note: This compound was somewhat volatile under high vacuum.
4-(Isoquinolin-1-yl)tetrahydro-2H-pyran-4-carbonitrile (1m). Pro-
cedure A: Tetrahydro-2H-pyran-4-carbonitrile (111 mg, 1.00 mmol)
and isoquinoline-1-carbonitrile (111 mg, 1.00 mmol) were reacted
with LiHMDS (1.1 mL) for 1.5 h. After workup, the compound was
pure, affording 1m as a white solid (232 mg, 97%): Rf = 0.31
(heptanes/EtOAc, 70:30); 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J =
8.5 Hz, 1H), 8.49 (d, J = 5.6 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.75−
7.64 (m, 3H), 4.17−4.03 (m, 4H), 2.56−2.43 (m, 4H); 13C NMR
(CDCl3, 126 MHz) δ 155.2, 141.1, 137.3, 130.0, 128.4, 127.6, 125.4,
124.7, 122.0, 121.8, 64.5, 42.0, 35.4; HRMS m/z calcd for C15H14N2O
[M + H]+ 239.1179, found 239.1200.
1-Benzyl 4-tert-Butyl 4-(3-Chloropyridin-4-yl)piperidine-1,4-dicar-
boxylate (2d). Procedure B: 1-Benzyl 4-tert-butyl piperidine-1,4-
dicarboxylate (319 mg, 1.00 mmol) and 3-chloroisonicotinonitrile
(139 mg, 1.00 mmol) were reacted with KHMDS (2.2 mL) for 3 h.
Flash chromatography (heptanes/EtOAc 100:0−60:40) afforded 2d as
a colorless oil (121 mg, 28%): Rf = 0.22 (heptanes/EtOAc 70:30); 1H
NMR (500 MHz, CDCl3) δ 8.53 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H),
7.37−7.30 (m, 5H), 7.26−7.24 (m, 1H), 5.14 (s, 2H), 4.04−3.80 (m,
2H), 3.62−3.36 (m, 2H), 2.54−2.40 (m, 2H), 2.08−1.78 (m, 2H),
1.38 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 171.9, 155.3, 150.8,
149.5, 148.3, 136.7, 131.4, 128.5, 128.1, 128.0, 121.8, 82.1, 67.2, 49.2,
40.3 (br), 32.0, 27.8; HRMS m/z calcd for C23H27N2O4Cl [M + H]+
431.1732, found 431.1709.
1-(Isoquinolin-1-yl)cyclopropanecarbonitrile (1n). Procedure A:
Cyclopropanecarbonitrile (67 mg, 1.00 mmol) and isoquinoline-1-
carbonitrile (154 mg, 1.00 mmol) were reacted with LiHMDS (1.1
mL) for 3 h. Flash chromatography (CH2Cl2/MeOH 100:0−95:5)
afforded 1n as a yellow solid (73 mg, 37%): Rf = 0.24 (heptanes/
1-tert-Butyl 3-Methyl 3-(3-Bromopyridin-4-yl)azetidine-1,3-dicar-
boxylate (2e). Procedure B: 1-tert-Butyl 3-methyl azetidine-1,3-
dicarboxylate (215 mg, 1.00 mmol) and 3-bromoisonicotinonitrile
(183 mg, 1.00 mmol) were reacted with KHMDS (2.2 mL) for 11 h.
Flash chromatography (heptanes/EtOAc 100:0−50:50) afforded 2e as
1
EtOAc 80:20); H NMR (500 MHz, CDCl3) δ 8.62−8.57 (m, 1H),
1
a clear oil (144 mg, 39%): Rf = 0.31 (Heptanes/EtOAc 50:50); H
8.42 (d, J = 5.7 Hz, 1H), 7.91−7.86 (m, 1H), 7.78−7.72 (m, 2H), 7.65
(d, J = 6.2 Hz, 1H), 1.89−1.85 (m, 2H), 1.80−1.76 (m, 2H); 13C
NMR (126 MHz, CDCl3) δ 152.9, 141.6, 136.7, 130.6, 128.2, 127.6,
127.3, 125.0, 122.7, 121.8, 16.0, 14.4; HRMS m/z calcd for C13H10N2
[M + H]+ 195.0917, found 195.0948.
NMR (500 MHz, CDCl3, 335 K) δ 8.70 (d, J = 1.9 Hz, 1H), 8.57 (dd,
J = 4.9, 1.9 Hz, 1H), 7.24 (d, J = 4.9 Hz, 1H), 4.57 (d, J = 8.8 Hz, 2H),
4.30 (d, J = 8.8 Hz, 2H), 3.73 (s, 3H), 1.45 (s, 9H); 13C NMR (126
MHz, CDCl3, 335 K) δ 171.4, 155.9, 152.8, 148.7, 147.3, 123.3, 121.7,
80.4, 57.0 (br), 53.3, 48.3, 28.4; HRMS m/z calcd for C15H19N2O4Br
[M + H]+ 371.0601, found 371.0586.
General Procedure for SNAr Reactions B (Table 2). The azine
(1 equiv) and, if solid, ester (1 equiv) were weighed into a vial and
purged with nitrogen gas. Anhydrous THF (2.5 mL) was added and
the mixture was cooled to −78 °C (dry ice, acetone) with stirring. If
the ester was a liquid, it was added at this point. Potassium
bis(trimethylsilyl)amide (1.1 equiv, 0.5 M in toluene [untitrated]) was
added before removal of the cooling bath and the reaction mixture
allowed to warm to rt. After completion as determined by TLC or
UPLC analysis, the mixture was quenched with satd aq NH4Cl and
diluted with CH2Cl2, and the layers were partitioned. The aqueous
layer was extracted with CH2Cl2 (2×), and the organic phases were
combined, dried (MgSO4), and concentrated to dryness. The resulting
residue was purified by flash chromatography using the stated eluent
system.
(1R*,5S*,6S*)-3-tert-Butyl 6-ethyl 6-(2,6-Dichloropyridin-4-yl)-3-
azabicyclo[3.1.0]hexane-3,6-dicarboxylate (2f). Procedure B:
(1R*,5S*,6S*)-3-tert-Butyl 6-ethyl 3-azabicyclo[3.1.0]hexane-3,6-di-
carboxylate (158 mg, 0.619 mmol) and 2,6-dichloroisonicotinonitrile
(132 mg, 0.742 mmol) were reacted with LiHMDS (1.4 mL, 1.4
equiv) for 17 h. Flash chromatography (heptanes/EtOAc, 100:0−
70:30) afforded 2f as a yellow solid (110 mg, 44%): Rf = 0.32
1
(Heptanes/EtOAc, 70:30); H NMR (500 MHz, CDCl3) δ 7.14 (s,
2H), 4.16 (q, J = 7.1 Hz, 2H), 4.03 (d, J = 11.3 Hz, 1H), 3.94 (d, J =
11.3 Hz, 1H), 3.50−3.40 (m, 2H), 2.14−2.03 (m, 2H), 1.42 (s, 9H),
1.33−1.26 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 166.2,
153.9, 153.3, 150.9, 121.2, 80.1, 62.0, 46.0 (br), 35.3, 30.3 (br), 28.3,
14.1; HRMS m/z calcd for C18H22N2O4Cl2 [M + H]+ 401.1029, found
401.1012.
Ethyl 1-(Pyridin-4-yl)cyclobutanecarboxylate (2a). Procedure B:
Ethyl cyclobutanecarboxylate (128 mg, 1.00 mmol) and isonicotinoni-
766
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The Journal of Organic Chemistry
Note
Ethyl 1-Benzyl-3-(6-Chloropyridin-2-yl)pyrrolidine-3-carboxylate
(2g). Procedure B: Ethyl 1-benzylpyrrolidine-3-carboxylate (233 mg,
1.00 mmol) and 6-chloropicolinonitrile (139 mg, 1.00 mmol) were
reacted with KHMDS (2.2 mL) for 19.5 h. Flash chromatography
(heptanes/EtOAc 100:0−70:30) afforded 2g as a yellow oil (186 mg,
54%): Rf = 0.32 (heptanes/EtOAc 70:30); 1H NMR (500 MHz,
CDCl3) δ 7.58 (dd, J = 7.8, 7.8 Hz, 1H), 7.36−7.29 (m, 4H), 7.26−
7.22 (m, 2H), 7.17 (d, J = 7.4 Hz, 1H), 4.23−4.07 (m, 2H), 3.72−3.63
(m, 2H), 3.33 (d, J = 9.7 Hz, 1H), 3.06 (d, J = 9.7 Hz, 1H), 2.91−2.76
(m, 2H), 2.76−2.68 (m, 1H), 2.43−2.34 (m, 1H), 1.19 (t, J = 7.1 Hz,
3H); 13C NMR (CDCl3, 126 MHz) δ 173.9, 162.8, 150.2, 139.0,
139.0, 128.5, 128.2, 126.9, 122.4, 119.8, 62.0, 61.4, 60.1, 59.7, 53.5,
34.6, 14.0; HRMS m/z calcd for C19H21N2O2Cl [M + H]+ 345.1364,
found 345.1345.
water (0.15 mL) and toluene (1.5 mL), and the vial was sealed. The
reaction mixture was stirred at 100 °C for 17 h. After the mixture was
concentrated to dryness, purification via flash chromatography
(heptanes/EtOAc 100:0−70:30) afforded 3a as a colorless oil (107
1
mg, 94%): Rf = 0.31 (heptanes/EtOAc 70:30); H NMR (500 MHz,
CDCl3) δ 8.47−8.42 (m, 1H), 7.27−7.25 (m, 1H), 7.11−7.06 (m,
1H), 4.12−3.78 (m, 1H), 3.77−3.60 (m, 1H), 3.47−3.23 (m, 2H),
2.24−1.92 (m, 7H), 1.50 (br s, 9H), 1.13−0.98 (m, 4H); 13C NMR
(126 MHz, CDCl3) δ 164.1 (br), 155.4 (br), 150.1, 150.0 (br), 120.8,
118.2, 117.0 (br), 80.1 (br), 46.9 (br), 45.3 (br), 42.6 (br), 41.0 (br),
37.0 (br), 28.5, 24.2 (br), 17.3 (br), 10.3 (br); HRMS m/z calcd for
C20H27N3O2 [M + H]+ 342.2176, found 342.2165.
tert-Butyl 4-(2-(2-Aminopyrimidin-5-yl)pyridin-4-yl)-4-cyanoaze-
pane-1-carboxylate (3b). Into a vial were weighed tert-butyl 4-(2-
chloropyridin-4-yl)-4-cyanoazepane-1-carboxylate (113 mg, 0.337
mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-
dichloropalladium(II) (11.9 mg, 5 mol %), 2-aminopyrimidine-5-
boronic acid pinacol ester (112 mg, 0.506 mmol), and potassium
carbonate (140 mg, 1.01 mmol). The vial contents were purged with
nitrogen gas before addition of distilled water (0.2 mL) and toluene
(1.1 mL), and the vial was sealed. The reaction mixture was stirred at
100 °C for 19 h. After the mixture was concentrated to dryness,
purification via flash chromatography (CH2Cl2/MeOH 100:0−90:10)
afforded 3b as a white solid (73.9 mg, 56%): Rf = 0.27 (CH2Cl2/
MeOH 95:5); 1H NMR (500 MHz, DMSO-d6, 335 K) δ 8.96 (s, 2H),
8.64 (d, J = 5.2 Hz, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.42 (dd, J = 5.2, 1.7
Hz, 1H), 6.91 (br s, 2H), 3.80−3.31 (m, 4H), 2.41−1.87 (m, 6H),
1.44 (s, 9H); 13C NMR (126 MHz, DMSO-d6, 335 K) δ 163.5, 156.4,
154.2, 153.7, 151.3, 150.1, 120.6, 120.6 (br), 118.3, 114.9, 78.6, 44.5,
42.1 (br), ∼39.6 (under DMSO), 37.0 (br), 38.2, 37.0 (br), 28.0, 24.8;
HRMS m/z calcd for C21H26N6O2 [M + H]+ 395.2190, found
395.2181.
Methyl 2-(Isoquinolin-1-yl)-2-methylpropanoate (2h). Procedure
B: Methyl isobutyrate (102 mg, 1.00 mmol) and isoquinoline-1-
carbonitrile (154 mg, 1.00 mmol) were reacted with KHMDS (2.2
mL) for 3 h. Flash chromatography (heptanes/EtOAc 100:0−70:30)
afforded 2h as a white solid (127 mg, 55%): Rf = 0.43 (heptanes/
1
EtOAc 80:20); H NMR (500 MHz, CDCl3) δ 8.50−8.43 (m, 1H),
7.93 (d, J = 8.7 Hz, 1H), 7.84−7.77 (m, 1H), 7.64−7.57 (m, 1H),
7.56−7.49 (m, 2H), 3.58 (s, 3H), 1.80 (s, 6H); 13C NMR (126 MHz,
CDCl3) δ 178.6, 161.5, 141.0, 136.8, 129.3, 128.0, 127.1, 126.2, 124.8,
120.5, 52.4, 49.7, 26.7; HRMS m/z calcd for C14H15NO2 [M + H]+
230.1176, found 230.1211.
3-(Isoquinolin-1-yl)-3-methyldihydrofuran-2(3H)-one (2i). Proce-
dure B: 3-Methyldihydrofuran-2(3H)-one (300 mg, 3.00 mmol) and
isoquinoline-1-carbonitrile (463 mg, 3.00 mmol) were reacted with
KHMDS (6.6 mL) for 2 h. Flash chromatography (heptanes/EtOAc
100:0−70:30) afforded 2i as a white solid (641 mg, 94%): Rf = 0.23
1
(heptanes/EtOAc 70:30); H NMR (500 MHz, CDCl3) δ 8.47−8.43
(m, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.70−7.65
(m, 1H), 7.64−7.58 (m, 2H), 4.46−4.40 (m, 1H), 4.29−4.23 (m, 1H),
3.23−3.15 (m, 1H), 2.54−2.47 (m, 1H), 1.97 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 180.1, 158.6, 140.9, 137.6, 129.7, 128.5, 127.2, 125.3,
125.2, 121.2, 65.7, 51.7, 38.0, 23.4; HRMS m/z calcd for C14H13NO2
[M + H]+ 228.1019, found 228.1004.
tert-Butyl 4-Cyano-4-(2-(pyridin-2-ylamino)pyridin-4-yl)azepane-
1-carboxylate (3c). Into a vial were weighed tert-butyl 4-(2-
chloropyridin-4-yl)-4-cyanoazepane-1-carboxylate (111 mg, 0.330
mmol), 2-aminopyridine (43.5 mg, 0.462 mmol), tris-
(dibenzylideneacetone)dipalladium(0) (7.6 mg, 2.5 mol %), 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene (11.5 mg, 6 mol %),
and cesium carbonate (150 mg, 0.462 mmol). The vial was purged
with nitrogen gas before anhydrous 1,4-dioxane (1.32 mL, 0.25 M)
was injected and the vessel sealed. The reaction mixture was stirred at
80 °C for 17 h before being cooled to rt, filtered through Celite, and
rinsed with CH2Cl2. After concentration, flash column chromatog-
raphy (CH2Cl2/MeOH, 100:0−95:5) afforded 3c as a colorless liquid
Racemic (1S*,2S*,4S*)-tert-Butyl 2-(Isoquinolin-1-yl)-
bicyclo[2.2.1]hept-5-ene-2-carboxylate (2j). Procedure B: Racemic
tert-butyl-5-norbornene-2-carboxylate (194 mg, 1.00 mmol) and
isoquinoline-1-carbonitrile (154 mg, 1.00 mmol) were reacted with
KHMDS (2.2 mL) for 3 h. Flash chromatography (heptanes/EtOAc
100:0−90:10) afforded 2j as a clear oil (129 mg, 40%): Rf = 0.41
(heptanes/EtOAc 90:10); 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J =
5.7 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.64−
7.59 (m, 1H), 7.54−7.48 (m, 2H), 6.52−6.45 (m, 1H), 6.14−6.07 (m,
1H), 4.23−4.17 (m, 1H), 3.03−2.90 (m, 1H), 2.74−2.64 (m, 1H),
2.02−1.91 (m, 1H), 1.72−1.62 (m, 2H), 1.13 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 173.8, 162.6, 141.2, 140.9, 136.7, 133.1, 129.3, 127.5,
127.4, 126.7, 126.3, 119.7, 80.4, 60.8, 50.9, 49.5, 43.5, 38.9, 27.7;
HRMS m/z calcd for C21H23NO2 [M + H]+ 322.1802, found
322.1790.
3-Methyl-3-(pyrimidin-4-yl)dihydrofuran-2(3H)-one (2k). Proce-
dure B: 3-Methyldihydrofuran-2(3H)-one (100 mg, 1.00 mmol) and
pyrimidine-4-carbonitrile (105 mg, 1.00 mmol) were reacted with
LiHMDS (1.1 mL) for 3.5 h. Flash chromatography (CH2Cl2/MeOH
100:0−95:5) afforded 2k as an off-white solid (111 mg, 62%): Rf =
0.26 (CH2Cl2/MeOH, 95:5); 1H NMR (500 MHz, CDCl3) δ 9.19 (d,
J = 1.5 Hz, 1H), 8.75 (d, J = 5.3 Hz, 1H), 7.60 (dd, J = 5.3, 1.5 Hz,
1H), 4.47−4.31 (m, 2H), 3.15−3.04 (m, 1H), 2.43−2.30 (m, 1H),
1.68 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 178.5, 168.4, 158.6,
157.7, 118.4, 65.9, 49.5, 35.48, 23.5; HRMS m/z calcd for C9H10N2O2
[M + H]+ 179.0815, found 179.0805.
1
(120 mg, 93%): Rf = 0.28 (CH2Cl2/MeOH 95:5); H NMR (500
MHz, CDCl3, 335 K) δ 8.30−8.21 (m, 2H), 7.90 (br s, 1H), 7.88−
7.77 (m, 1H), 7.61−7.56 (m, 1H), 7.51−7.38 (m, 1H), 6.91 (m, 1H),
6.88−6.83 (m, 1H), 4.13−3.80 (m, 1H), 3.79−3.59 (m, 1H), 3.45
(ddd, J = 12.0, 4.3 Hz, 4.3 Hz, 1H), 3.42−3.25 (m, 1H), 2.22−1.97
(m, 6H), 1.50 (s, 9H); 13C NMR (CDCl3, 126 MHz, 335 K) δ 155.4
(br), 155.0, 154.0, 152.3, 148.7, 147.9, 137.8, 120.9, 116.8, 113.1,
112.0, 108.2, 80.0, 47.2 (br), 45.5 (br), 43.0 (br), 40.8 (br), 37.1 (br),
28.6, 24.4 (br); HRMS m/z calcd for C22H27N5O2 [M + H]+
394.2237, found 394.2214.
tert-Butyl 4-Cyano-4-(2-isopropoxypyridin-4-yl)azepane-1-car-
boxylate (3d). Into a vial were weighed tert-butyl 4-(2-chloropyr-
idin-4-yl)-4-cyanoazepane-1-carboxylate (108 mg, 0.323 mmol),
palladium(II) acetate (3.6 mg, 5 mol %), 5-(di(adamantan-1-
yl)phosphino)-1′,3′,5′-triphenyl-1′H-1,4′-bipyrazole (20 mg, 10 mol
%), and cesium carbonate (315 mg, 0.969 mmol). The vial was purged
with nitrogen gas before injection of anhydrous toluene (1.6 mL) and
anhydrous 2-propanol (250 μL, 3.23 mmol), and the vessel was sealed.
The reaction mixture was stirred at 120 °C for 19 h before being
cooled to rt, filtered through Celite, and rinsed with CH2Cl2. After
concentration, flash column chromatography (heptanes/EtOAc
100:0−75:25) afforded 3d as a colorless liquid (65 mg, 56%): Rf =
tert-Butyl 4-Cyano-4-(2-cyclopropylpyridin-4-yl)azepane-1-car-
boxylate (3a). Into a vial were weighed tert-butyl 4-(2-chloropyr-
idin-4-yl)-4-cyanoazepane-1-carboxylate (111 mg, 0.333 mmol),
palladium(II) acetate (3.7 mg, 5 mol %), n-butyldi-1-adamantylphos-
phine (8.9 mg, 7.5 mol %), potassium cyclopropyltrifluoroborate (54.1
mg, 0.366 mmol), and cesium carbonate (325 mg, 1.00 mmol). The
vial contents were purged with nitrogen gas before addition of distilled
1
0.29 (heptanes/EtOAc 80:20); H NMR (500 MHz, CDCl3) δ 8.13
(d, J = 5.1 Hz, 1H), 6.88 (d, J = 5.1 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H),
5.31 (hept, J = 6.2 Hz, 1H), 4.13−3.76 (m, 1H), 3.76−3.57 (m, 1H),
3.49−3.16 (m, 2H), 2.16−1.92 (m, 6H), 1.49 (s, 9H), 1.34 (d, J = 6.2
767
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The Journal of Organic Chemistry
Note
Hz, 6H); 13C NMR (CDCl3, 126 MHz, 335 K) δ 164.4, 155.4, 153.0,
147.9, 120.8, 113.2, 108.3, 80.0, 68.6, 46.8, 45.4, 42.9, 40.9, 37.1, 28.6,
24.4, 22.1; HRMS m/z calcd for C20H29N3O3 [M + H]+ 360.2282,
found 360.2274.
Guan, B.-T.; Li, B.-J.; Zheng, Y.; Wu, Z.-H.; Shi, Z.-J. Org. Lett. 2009,
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for compounds 1a−n, 2a−k, 3a−d.
This material is available free of charge via the Internet at
http://pubs.acs.org.
H.; Kita, Y.; Rem
115−118.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: huestis.malcolm@gene.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.D.T. thanks the Genentech undergraduate summer intern-
ship program. M.P.H. thanks Michael Siu for support and
encouragement, Chunang Gu and Desheng Wang for
acquisition of high-resolution mass spectral data, and Yanzhou
Liu for NMR spectroscopic assistance concerning the structural
identity of compounds 2f and 2j.
(12) (a) α-1A adrenergic receptor antagonists (Merck): Patane, M.
A.; DiPardo, R. M.; Newton, R. C.; Price, R. P.; Broten, T. P.; Chang,
R. S. L.; Ransom, R. W.; Di Salvo, J.; Nagarathnam, D.; Forray, C.;
Gluchowski, C.; Bock, M. G. Bioorg. Med. Chem. Lett. 2000, 10, 1621−
1624. (b) 11β-HSD1 inhibitors (Amgen): McMinn, D. L.; Rew, Y.;
Sudom, A.; Caille, S.; DeGraffenreid, M.; He, X.; Hungate, R.; Jiang,
B.; Jaen, J.; Julian, L. D.; Kaizerman, J.; Novak, P.; Sun, D.; Tu, H.;
Ursu, S.; Walker, N. P. C.; Yan, X.; Ye, Q.; Wang, Z.; Powers, J. P.
Bioorg. Med. Chem. Lett. 2009, 19, 1446−1450. (c) En route to
nociceptin receptor agonists (Schering-Plough): Yang, S.-W.; Ho, G.;
Tulshian, D.; Greenlee, W. J.; Fernandez, X.; McLeod, R. L.; Eckel, S.;
Anthes, J. Bioorg. Med. Chem. Lett. 2008, 18, 6340−6343. (d) Direct
precursor to Sanofi’s antiarrhythmic drug pentisomide: Bernhart, C.
A.; Condamine, C.; Demarne, H.; Roncucci, R.; Gagnol, J.-P.; Gautier,
P. J.; Serre, M. A. J. Med. Chem. 1983, 26, 451−455. (e) M1 receptor
modulators (Merck): ref 5b.
DEDICATION
■
Dedicated to the memory of Professor Keith Fagnou (1971−
2009).
REFERENCES
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768
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Note
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(24) In the control experiment, no reaction occurs in the absence of
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analysis of the reaction mixture.
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