Regioselective Iron-Catalyzed [2 + 2 + 2] Cycloaddition Reaction Forming 4,6-Disubstituted 2-Aminopyridines from Terminal Alkynes and Cyanamides

Article abstract of DOI:10.1021/acs.joc.6b02374

Iron complexes bound by redox-active pyridine dialdimine (PDAI) ligands catalyze the cycloaddition of two terminal alkynes and one cyanamide. The reaction is both chemo- and regioselective, as only 4,6-disubstituted 2-aminopyridine products are formed in moderate to high yields. Isolation of an iron azametallacycle (4) suggests that catalyst deactivation occurs with a large excess of cyanamide over longer reaction times. Fe-catalyzed cycloaddition allowed for a straightforward synthesis of a variety of aminopyridines, including known estrogen receptor ligands.

Full text of DOI:10.1021/acs.joc.6b02374

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Article
A Regioselective Iron-catalyzed [2+2+2] Cycloaddition Reaction Forming 4,6-
Disubstituted-2-Aminopyridines from Terminal Alkynes and Cyanamides
Nathan A. Spahn, Minh H. Nguyen, Jonas Renner, Timothy K. Lane, and Janis Louie
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02374 • Publication Date (Web): 17 Nov 2016
Downloaded from http://pubs.acs.org on November 18, 2016
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A Regioselective Iron-catalyzed [2+2+2] Cycloaddition Reaction Forming 4,6-Disubstituted-2-
Aminopyridines from Terminal Alkynes and Cyanamides
Nathan A. Spahn, Minh H. Nguyen, Jonas Renner, Timothy K. Lane, and Janis Louie*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT, 84112
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ABSTRACT: Iron complexes bound by redoxꢀactive pyridine dialdimine (PDAI) ligands catalyze the cycloaddition
of two terminal alkynes and one cyanamide. The reaction is both chemoꢀ and regioselective as only 4,6ꢀ
disubstitutedꢀ2ꢀaminopyridine products are formed in moderate to high yields. Isolation of a Feꢀazametallacycle (4)
suggests catalyst deactivation occurs with large excess of cyanamide over longer reaction times. Feꢀcatalyzed
cycloaddition allowed for a straightforward synthesis of a variety of aminoꢀpyridines, including known estrogen
receptor ligands.
Introduction. Metal-catalyzed [2+2+2] cycloaddition reactions represent a powerful synthetic tool for the construction
1
-6
of cyclic aromatic compounds in a single step. Indeed, a variety of substituted aromatic compounds including
7
-8
4-5,10-15
16
17-19
benzenes, pyridines,
pyrimidines, and pyranones
have been prepared through the use of transition metal
1
4,20-21
22,23
Rh,
24-28
Co,
29-31
Ir,
32
13,15,19,
33
34-36
10-12,16,37-42
catalysts based on Ru,
Mo, Ni,
Ti, Pd,
and Fe.
Of these metals, Co, Ni,
and Fe are particularly interesting because of their lower cost and wide availability. Despite the utility of this
transformation, almost all examples require the use of tethered pi-systems, typically in the form of a diyne, due to the
inherent difficulties in controlling both chemo- and regioselectivity. This is particularly true for synthetic strategies
that convert two alkynes and a nitrile into pyridine products as alkynes are inherently more reactive than nitrile
20,26,40-42
substrates.
Furthermore, when terminal alkynes are coupled with a nitrile in a [2+2+2] cycloaddition, four
different pyridine regioisomers and two benzene isomers are possible, as well as other alkyne oligomers. For example,
Rh-catalyzed cycloaddition of two terminal alkynes and cyanamides, an activated nitrile, produced a 1.3:1 mixture of 4,6-
23
and 3,6-disubstituted 2-amino pyridines. Similarly, equal amounts of 3,6- and 4,6-disubstituted-2-aminopyridine
26
products were formed in CoCp(CO) -catalyzed cycloadditions. Some recent metal-free reports of regioselective
2
[
2+2+2] cycloaddition reactions coupling ynamides and nitriles or to yield the corresponding pyridines in high yields
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3-44
have been reported.
Nevertheless, the development of a more general chemo- and regioselective cycloaddition
method for pyridine formation would represent a significant synthetic advance.
Our laboratory recently developed a Ni(COD) /SIPr (SIPr= 1,3-bis(2,6-diisopropylphenyl)imidazolidene)
2
system that successfully catalyzes the cycloaddition reaction of terminal alkynes and cyanamides to provide the 3,5-
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disubstituted-2-aminopyridine regioisomer as the major product with reasonable regiocontrol. Additionally, two
isolated reports of intermolecular Fe-catalyzed cycloaddition demonstrate chemo- and regioselective cycloadditions
1
1,12
between alkynes and nitriles may be possible (eqs 1-2) . Interestingly, these two Fe-systems suggest regioselectivity
may be controlled by choice of ligand. As such, we sought to define the generality of our chemo- and regioselective
Mes
Mes
three-component methodology catalyzed by
PDAI-bound
(
PDAI=(1E,1'E)-1,1'-(pyridine-2,6-diyl)bis(N-
mesitylmethanimine) Fe complexes.
aminopyridine products regioselectively.
Herein, we report reaction conditions that afford 4,6-disubstituted-2-
N
5
mol % FeCl2
0 mol % MesPDAI
1
N
N
10 mol % Zn
N
(1)
benzene, 50 ˚C, 6h
2
equiv.
90%
F
1
0 mol % FeI2
20 mol % dppp
N
N
20 mol % Zn
N
N
(2)
THF, rt
F
2
equiv.
F
70%
Results and Discussion. We initially focused on establishing a general cycloaddition protocol based on our Fe/PDAI
system (eq 1) using alkyne 1a and cyanamide 2a as model substrates (Table 2). Many [2+2+2] cycloaddition reactions
that couple two alkynes and a nitrile yield substituted benzenes as common side-products. Thus, we initially ran
reactions with excess cyanamide 2a. However, increasing the equivalence of cyanamide had no effect on the yield of
4
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pyridine product 3aa or reduction in the amount of alkyne trimers formed.
Instead, increased cyanamide
equivalents led to the formation of complex 4, an iron azametallacycle incorporating two cyanamides, over long
reaction times. It is important to note that only trace amounts of complex 4 are obtained after the first hour. An
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ORTEP diagram of complex 4 is shown in Figure 1 and selected bond lengths are shown in Table 1. Interestingly,
iPr
complex 4 shares important ligand bond lengths with an ( PDAI)Fe(DMAP) complex developed by Chirik and
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coworkers, which suggests the complex possesses a radical dianionic ligand and an iron(IV) center. The geometry of
complex 4 is distorted square pyramidal with the four iron-bound nitrogen atoms slightly out of the square plane with
iron and the axial carbon offset toward the azametallacycle nitrogen. Complex 4 represents the only example of an
isolated iron azametallacycle.
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iPr
Figure 1. ORTEP diagram of ( PDAI)Fe(NCNMe2)2 4
iPr
iPr
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Table 1. Comparison of selected bond lengths for ( PDAI)Fe(NCNMe2)2 and ( PDAI)Fe(DMAP)
(iPrPDAI)Fe(NCNMe2)2
(iPrPDAI)Fe(DMAP)a
Nimine - Cimine
Cimine - Cipso
1.334(2), 1.242(2)
1.416(2), 1.407(3)
1.383(2), 1.389(2)
1.9684(15)
1.339(3),1.355(3)
1.407(4), 1.406(4)
C
ipso - Npy
1.379(3), 1.373(3)
Fecycle - Ncycle
Fecycle - Ccycle
-
-
1.9956(17)
aData taken from reference 47
When alkyne 1a and cyanamide 2a were subjected to catalytic amounts of complex 4, only trace hexamethyl-
,3,5-triazine-2,4-6-triamine was observed along with unreacted starting materials (eq 3). As such, we believe complex 4
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is a catalyst sink, and large equivalents of cyanamide relative to Fe catalyst must be avoided to reduce formation of
azametallacycle 4.
5
mol %
N
Fe
N
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N
Ar
Ar
N
N
N
N
N
N
2a
N
N
N
N
Ph
N
4
(
3)
N
N
benzene
N
Ph
Ph
not detected
1a
trace
5 mol % FeI2
10 mol % MesPDAI
10 mol % Zn
N
N
N
N
(4)
toluene, rt, 0.4 M
88%
3
equiv.
1a
2a
3aa
In contrast, increasing the amount of alkyne relative to cyanamide successfully increased the yield of pyridine
products. Three equivalents of alkyne led to greater consumption of cyanamide, while further equivalents of alkyne
failed to increase the pyridine yields (eq 4). We also determined that zinc serves as a reductant for the iron halide pre-
Mes
47
catalyst. That is, when 1a and 2a were combined with 5 mol% ( PDAI)Fe(C H ) in the absence of zinc, 3aa was
4
6
obtained in an isolated yield of 80%. Nevertheless, we felt our optimized cycloaddition protocol with in situ formation
of the Fe catalyst in the presence of zinc would be more practical and employed these conditions on a variety of alkynes
and cyanamides (Table 2). The iron system is effective at coupling both aryl- and alkyl-substituted alkynes, which is a
1
5
marked improvement over our Ni/IPr system that preferentially reacts with alkyl-substituted alkynes. The substitution
pattern of the pyridine regioisomers were easily determined by 1D-NOESY NMR spectroscopy (see Supp Info). Yields in
parentheses are adjusted relative to unreacted cyanamide. The unreacted cyanamide suggests that alkyne trimerization
rates are comparable to the rate of cyclization between alkyne and cyanamide resulting in alkyne consumption prior to
complete cyanamide conversion. Aryl alkynes reacted with dimethyl cyanamide 1a to exclusively afford 4,6-
aminopyridine products in high yields (Table 2, entries 1-6). Ortho-substitution (1c) on the aryl alkyne did not affect
product yield. However, no conversion was observed when doubly ortho-substituted aryl alkynes such as 2,4,6-
trimethylphenylacetylene was used as the cycloaddition partner. Both electron-donating and electron-withdrawing
groups on the aryl ring were tolerated (entries 4-5) though slightly lower yields were obtained with electron-
4
8,49
withdrawing substituents. Although low-valent Fe complexes are known to activate aryl halides,
both 4-fluroro-1-
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ethynylbenzene and 4-chloro-1-ethynylbenzene were amenable substrates (entries 5-6). Not surprisingly, high yields of
2-aminopyridine products were obtained when diethyl cyanamide 2b and pyrrolidine-1-carbonitrile 2c (entries 7-8).
Interestingly, lower yields were obtained when six-membered cyanamides, such as piperidine-1-carbonitrile 2d and
morpholine-4-carbonitrile 2e, were used as coupling partners. Cyanamides possessing easily removable groups, such as
allyl (2f) and benzyl (2g), were also successfully converted to pyridine products (entries 11-12). However, attempts at
using other protected cyanamides, such as tert-butylcarbamate and N-tosyl cyanamide, did not yield pyridine product,
which is likely due to less electron density at the nitrile nitrogen. In addition, when acetonitrile was used instead of
cyanamide, only alkyne oligomers were observed.
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a
Table
2.
Iron
catalyzed
[2+2+2]
cycloaddition
of
terminal
alkynes
and
cyanamides
Entry
Alkyne Cyanamide
Product
R'
Yield(%)c Entry
Alkyne Cyanamide
R
Product
Yield
(%)c
R
R
N
Ph
N
R
N
R'
R
N
N
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
1a
12a
32 (71)
78(82)
1
1a
R'
R=allyl 2f
R=allyl 3af
R=Bn 3ag
R
1a
R=Bn 2g
N
N
R
1a
2a
3a
R
2a
R=H, R'=H 3aa
R=Me, R'=H 3ba
R=H, R'=Me 3ca
R=OMe, R'=H 3da 98
R=F, R'=H 3ea
R=Cl, R'=H 3fa
88 (93)
82 (83)
89
R=H, R'=H 1a
R=Me, R'=H 1b
R=H, R'=Me 1c
R
2a
2a
2a
2a
2a
4a R=OMe, R'=H 1d
5a
6a
R
13b
69 (91)
62 (82)
R=CH2CH3 1g
R=OTBS 1h
2
2a
a
R=CH2CH3 3ga
R=OTBS 3ha
R=CH OTBS 3ia
55 (92)
83 (89)
69 (>95)
59 (>95)
R=F, R'=H 1e
R=Cl, R'=H 1f
4b
1
1
1
5b R=CH OTBS 1i 2a
2
2
Et
6c
R=CH Ph 1j
2a
2a
R=CH Ph 3ja
2
2
Ph
Ph
N
Et
Et
TMS
N
7
0
N
7a
1a
1a
N
17b
18b
19b
60
(89)
Et
(>95)
TMS
N
N
2b
1k
Ph
3ab
TMS
3ka
N
N
N
86
8a
N
N
(87)
N
54
(76)
2a
2a
2c
Ph
3ac
1l
3
la
R
S
R
Ph
N
N
N
N
N
N
69
S
Ph
(>95)
1m
9a
R=CH 2d
R=CH 3ad
44 (83)
48 (>95)
1a
1a
2
2
2e
R=O 3ae
S
0a
R=O
1
3ma
a5 mol % FeI , 10 mol % MesPDAI, 10 mol % Zn, 3 equiv. alkyne, 0.4 M cyanamid, toluene, rt
2
b5 mol % FeI , 10 mol % MesPDAI, 10 mol % Zn, 3 equiv alkyne added dropwise over 3 hours, 0.4 M cyanamide, toluene, rt
2
cIsolated yields, brsm yields in parenthessis
Unlike our Ni system which preferentially converted alkyl alkynes over aryl alkynes, the Fe/PDAI combination
effectively catalyzes the cycloaddition of both aryl alkynes and alkyl alkynes. For alkyl alkynes, slow addition of the
alkyne over the course of three hours ensured pyridine product formation over cyclotrimerization of alkyl alkynes.
Catalyst deactivation through complex 4 does not occur because it does not appreciably form at shorter reactions times.
Oxygen functional groups, such as protected alcohols 1h and 1i, as well as alkynes possessing a distal aromatic group
(
1j) were successfully employed in the cycloaddition reaction to yield the corresponding 2-amino pyridines in good
yields (entries 14-16). Pyridine products were also formed from the use of trimethylsilyl protected acetylene (entry 17)
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and ethynylcyclopropane (entry 18). The use of propargyl chloride as a coupling partner shut down the cycloaddition,
which is likely due to irreversible oxidation of the Fe catalyst. Adding substitution to the 3 position of the terminal
alkynes and when using methyl propiolate afforded only alkyne oligomers, despite slow addition of alkyne. To our
surprise, sulfur-containing 3-ethynylthiophene 1m was also converted to pyridine product, despite iron’s propensity to
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5
0
bind sulfur compounds (entry 19).
4,6-Diaryl-2-aminopyridine pyridines are known estrogen receptor ligands for both the alpha and beta
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receptor proteins (ERα and ERβ). We believed that we could apply our Fe-catalyzed cycloaddition methodology to
construct the pyridine core of one of these compounds in a single step. Thus, we subjected tert-butyl(4-
ethynylphenoxy)dimethylsilane and N-methyl-N-phenethylcyanamide to the standard cycloaddition conditions, and,
gratifyingly, the corresponding protected estrogen receptor was isolated in 76% yield (Scheme 1). After deprotection
with KOH, the estrogen receptor ligand was isolated in 70% overall yield over two steps. This Fe-catalyzed
cycloaddition protocol is a marked improvement over the previous synthetic pathway which is a four step process with
51
an overall yield of 35%.
TBSO
mol % FeI2
0 mol % MesPDAI
Ph
5
N
1
N
N
10 mol % Zn
N
toluene, rt
Ph
TBSO
1n
2h
3
equiv. KOH
EtOH
OTBS
HO
3
nh 76 %
Ph
N
N
OH
5
92 %
Scheme 1. Fe-catalyzed cycloaddition approach to an estrogen
receptor ligand
In conclusion, we have presented a general [2+2+2] cycloaddition that exhibits unprecedented exclusive
selectivity for the 4,6-disubstituted-2-aminopyridines. The reaction is synthetically practical and tolerant of both aryl
and alkyl substituted alkynes as well as a variety of functional groups. Additional experiments are being conducted to
determine selectivity for mixed pyridine products when two different terminal alkynes are employed. In addition, the
regioselective Fe-catalyzed cycloaddition protocol was used to prepare known estrogen substitutes and ligands for the
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ERα and ERβ proteins. The mechanism of this catalyst system and the origin of the regioselectivity are currently being
explored by our laboratory.
Experimental Section
General Experimental: All reactions were conducted in a N2 filled glove-box unless otherwise noted. Toluene was
dried over neutral alumina under N2 using a Grubbs type solvent purification system. FeI2 was purchased from Sigma-
Aldrich and used without further purification. MesPDAI was synthesized via literature methods. All alkynes and
cyanamides were purchased form commercial sources. Liquid cyanamides and alkynes were degassed using three
sequential freeze-pump thaw cycles. 1H and 13C Nuclear Magnetic Resonance spectra of pure compounds were
acquired at 400 and 101 MHz respectively, unless otherwise noted. All spectra are referenced to a singlet at 7.26 ppm for
0
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1H and to the center line of a triplet at 77.0 ppm for 13C. The abbreviations s, d, dd, dt, dq, t, q, and quint stand for
singlet, doublet, doublet of doublets, doublet of triplets, doublet of quartets, triplet, quartet, and quintet, respectively.
All 13C NMR spectra were proton decoupled. Preparatory TLC was performed on Silica Gel TLC plates 60 F256 from
Merk KGaA. IR spectra were obtained using a Bruker Tensor 27 spectrometer on KBr discs. Calculated HRMS data was
obtained from ChemDraw software.
Method A. In a nitrogen-filled glovebox, 2 mL vial was charged with iron iodide (0.05 equiv.) and MesPDAI ((1E,1'E)-
1,1'-(pyridine-2,6-diyl)bis(N-mesitylmethanimine)) (0.10 equiv.) and toluene to bring the final molarity to 0.4 M. The
catalyst solution was stirred for 20 minutes at which time cyanamide (1 equiv.) was added. The reaction was stirred for
5 minutes before zinc (0.1 equiv.) was added. The reaction was stirred for another 5 minutes and alkyne (3 equiv.) was
added. The reaction was stirred overnight and the crude reaction mixture passed through a Celite plug. The product
was isolated by preparatory TLC.
Method B. In a nitrogen-filled glovebox, 2 mL vial was charged with iron iodide (0.05 equiv.) and MesPDAI ((1E,1'E)-
1
,1'-(pyridine-2,6-diyl)bis(N-mesitylmethanimine)) (0.10 equiv.) and toluene to bring the final molarity to 0.4 M. The
catalyst solution was stirred for 20 minutes at which time cyanamide (1 equiv.) was added. The reaction was stirred for
minutes before zinc (0.1 equiv.) was added. The reaction was stirred for another 5 minutes and alkyne (3 equiv.) was
5
added by syringe pump over 3 hours. The reaction was stirred overnight and the crude reaction mixture passed
through a Celite plug. The product was isolated by preparatory TLC.
iPr
Synthesis of Complex 4. In a nitrogen-filled glovebox, a vial was charged with ( PDAI)FeBr2 (1 equiv., 100 mg, 0.15
mmol) and 0.25 mL of toluene and a stir bar was added to the vial. Cyanamide 1a (10 equiv., 121 µL, 1.5 mmol) was
added to the vial and the resulting reaction was stirred for 30 minutes. Sodium mercury amalgam or zinc (2.5 equiv.)
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was added to the vial and the reaction was allowed to stir overnight. The resulting solution was passed through Celite
and residual reactant in the reaction vial was dissolved with THF and also passed through Celite. All solvents were
removed in vacuo. Pentane was added to the residue and the heterogeneous solution was again passed through Celite.
Pentane was allowed to slowly evaporate at room temperature to give green crystals of Complex 4.
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Synthesis of N,N-dimethyl-4,6-diphenylpyridin-2-amine (3aa)
Mes
Method A for the cycloaddition was used with iron iodide (2.8 mg, 0.0091 mmol), PDAI (6.7
N
mg, 0.0182 mmol), alkyne 1a (60 μL, 0.546 mmol), and cyanamide 2a (14.8 μL, 0.182 mmol). The
N
product was isolated by preparatory TLC (10% ethyl acetate in hexanes, Rf = 0.6) in 88% (43.9 mg)
1
yield of pyridine 3aa as a yellow oil. H NMR (400 MHz, CDCl ) δ 8.14 (d, J = 7.5 Hz, 2H), 7.70 (d, J
3
13
=
7.3 Hz, 2H) 7.52 – 7.39 (m, 6H), 7.29 (s, 1H), 6.68 (s, 1H), 3.25 (s, 6H). C (75 MHz, CDCl ) δ 159.6, 155.5, 150.6, 140.3,
3
-
1
1
40.2, 128.8, 128.5, 128.4, 127.1, 126.9 (2C), 107.2, 102.5, 38.1. IR (cm ) 3059, 3035, 2925, 2853, 1598, 1547, 1499, 1250, 1183.
+
HRMS (ESI) m/z calcd for C H N [M+H] 275.1543, found 275.1541.
1
9
18
2
1D NOESY Relationships
11
Synthesis of N,N-dimethyl-4,6-di-p-tolylpyridin-2-amine (3ba)
Method A for the cycloaddition reaction was used with iron iodide (2.5 mg, 0.00825 mmol),
Mes
PDAI (6.1 mg, 0.0165 mmol) alkyne 1b (62.8 μL, 0.495 mmol), and cyanamide 2a (13.4 μL, 0.165
mmol). The crude product was purified by preparatory TLC (10% ethyl acetate in hexanes, Rf =
1
0.6) in 82% (41.0 mg) yield of pyridine 3ba as a yellow oil. H NMR (400 MHz, CDCl ) δ 8.00 (d, J
3
=
7.8 Hz, 2H), 7.57 (d, J = 7.7 Hz, 2H), 7.25-7.23 (m, 5H), 6.61 (s, 1H), 3.20 (s, 6H), 2.41 (s, 3H), 2.40
1
3
(
(
3
s, 3H). C NMR (75 MHz, CDCl ) δ 159.6, 155.5, 138.3, 237.5, 137.4, 129.5, 129.1, 126.9, 126.7, 106.8, 101.9, 38.1, 21.3, 21.2. IR
3
-1
+
cm ) 3027, 2922, 2858, 2803, 1600, 1545, 1512, 1417, 1401, 1182. HRMS (ESI) m/z calcd for C H N [M+H] 303.1856, found
2
1
23
2
03.1863.
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Synthesis of N,N-dimethyl-4,6-di-o-tolylpyridin-2-amine (3ca)
Mes
Method A for the cycloaddition was used with iron iodide (2.5 mg, 0.00825 mmol), PDAI (6.1
mg, 0.0165 mmol), alkyne 1c (62.4 μL, 0.495 mmol), and cyanamide 2a (13.4 μL, 0.165 mmol). The
crude product was purified by preparatory TLC (10% ethyl acetate in hexanes, Rf = 0.6) in 89%
1
(
44.5) yield of pyridine 3ca as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.53 (dd, J = 5.3, 1.8 Hz,
3
1
3
1H) 7.47-7.22 (m, 7H), 6.70 (s, 1H), 6.44 (s, 1H), 3.18 (s, 6H), 2.54 (s, 3H), 2.37 (s, 3H). C (75 MHz, CDCl ) δ 158.8, 157.7,
3
-
1
151.1, 141.2, 140.9, 136.1, 135.1, 130.7, 130.4, 129.7, 129.1, 127.74, 127.71, 125.8, 125.6, 113.1, 104.0, 38.1, 20.9, 20.4.. IR (cm ) 3060,
+
3019, 2924, 2855, 1595, 1574, 1547, 1497, 1401, 1379, 1122. HRMS (ESI) m/z calcd for C H N [M+H] 303.1856, found
21
22
2
3
03.1861.
1D NOESY Relationships
Synthesis of 4,6-bis(4-methoxyphenyl)-N,N-dimethylpyridin-2-amine (3da)
Method A for the cycloaddition reaction was used with iron iodide (2.3 mg, 0.0075 mmol),
Mes
PDAI (5.5 mg, 0.015 mmol), alkyne 1d (58.4 μL, 0.450 mmol), cyanamide 2a (12.2 μL, 0.150
mmol). The product was isolated by preparatory TLC (10% ethyl acetate and hexanes, Rf =
1
0
.6) in 98% (49.0 mg) yield of pyridine 3da as a yellow solid. mp 122-125 °C; H NMR (400
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MHz, CDCl ) δ 8.07 (d, J = 8.8 Hz, 2H), 7.67-7.60 (m, 2H), 7.19 (s, 1H), 7.05-6.96 (m, 4H), 6.59 (s, 1H), 3.97 (s, 6H), 3.22
3
1
3
(
s, 6H). C (101 MHz, CDCl ) δ 160.1, 160.0, 159.6, 155.2, 150.1, 133.0, 132.8, 128.2, 128.1, 114.2, 113.7, 106.2, 101.3, 55.34, 55.29,
3
-
1
+
38.1. IR (cm ) 3027, 2922, 2855, 1601, 1546, 1513, 1417, 1400, 1183. HRMS (ESI) m/z calcd for C H N O [M+H] 335.1754,
21
22
2
2
found 335.1758.
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60
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Synthesis of 4,6-bis(4-fluorophenyl)-N,N-dimethylpyridin-2-amine (3ea)
Method A for the cycloaddition reaction was used with iron iodide (2.5 mg, 0.00805 mmol),
Mes
PDAI (5.9 mg, 0.0161 mmol), alkyne 1e (55.4 μL, 0.483 mmol), and cyanamide 2a (13.1 μL,
0.161 mmol). The crude product was purified by preparatory TLC (10 % ethyl acetate in
1
hexanes, Rf = 0.5) in 69% (34.5 mg) yield of pyridine 3ea as a white solid. mp 128-129 °C; H
NMR (400 MHz, CDCl ) δ 8.16-8.03 (m, 2H), 7.73-7.58 (m, 2H), 7.24-7.07 (m, 5H), 6.58 (s, 1H),
3
1
3
3
.22 (s, 6H). C (75 MHz, CDCl ) δ 163.3 (J = 246.0 Hz), 163.1 (JC-F = 246.0 Hz), 159.5, 154.6, 149.7, 136.3 (JC-F = 3.3 Hz),
3 C-F
136.2 (JC-F = 3.0 Hz), 128.8 (JC-F = 8.2 Hz), 128.6 (JC-F = 8.2 Hz), 115.7 (JC-F = 21.5 Hz), 115.3 (JC-F = 21.5 Hz), 106.6, 102.2, 38.1.
-1
+
IR (cm ) 3068, 2926, 2854, 1607, 1550, 1508, 1399, 1294, 1185, 1156. HRMS (ESI) m/z calcd for C H F N [M+H] 311.1354,
19
16
2
2
found 311.1358.
1D NOESY Relationships
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Synthesis of 4,6-bis(4-chlorophenyl)-N,N-dimethylpyridin-2-amine (3fa)
Method A for the cycloaddition reaction was used with iron iodide (2.3 mg, 0.0073 mg),
Cl
Mes
PDAI (5.4 mg, 0.0146 mmol), alkyne 1f (59.8 mg, 0.438 mmol), and cyanamide 2a (11.9 μL,
N
N
0.146 mmol). The crude product was purified by preparatory TLC (10% ethyl acetate in
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hexanes, Rf = 0.4) in 62% (31.0 mg) yield of pyridine 3fa as a white solid. mp 157-160 °C; H
NMR (400 MHz, CDCl ) δ 8.03 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.45-7.50 (m, 4H),
3
Cl
13
7
.15 (s, 1H), 6.59 (s, 1H), 3.22 (s, 6H). C (75 MHz, CDCl ) δ 159.5, 154.5, 149.5, 138.5, 138.4, 134.6, 134.5, 129.0, 128.6, 128.4,
3
-1
+
1
28.1, 106.6, 102.4, 38.1. IR (cm ) 2924, 2852, 1603, 1546, 1490, 1417, 1396. HRMS (ESI) m/z cacld for C H Cl N [M+H]
1
9
16
2
2
343.0763, found 343.0771.
1D NOESY Relationships
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Synthesis of N,N-diethyl-4,6-diphenylpyridin-2-amine (3ab)
Mes
Method A for the cycloaddition was used with iron iodide (2.8 mg, 0.0090 mmol), PDAI (6.7
mg, 0.0180 mmol), alkyne 1a (59.3 μL, 0.540 mmol), and cyanamide 2b (20.9 μL, 0.180 mmol).
The product was isolated by preparatory TLC (5% ethyl acetate in hexanes, Rf = 0.6) in 70%
1
(
35.0 mg) yield of pyridine 3ab as a yellow oil. H NMR (400 MHz, CDCl ) δ 8.15-8.07 (m, 2H),
3
1
3
7.71-7.64 (m, 2H), 7.52-740 (m, 6H), 7.22 (s, 1H), 6.60 (s, 1H), 3.68 (q, J = 7.0 Hz, 4H), 1.29 (t, J = 7.0 Hz, 6H). C (101
-
1
MHz, CDCl ) δ 157.7, 155.7, 150.6, 140.6, 140.4, 131.3, 128.8, 128.4, 128.3, 127.1, 126.8, 106.7, 102.2, 42.7, 13.2. IR (cm ) 2959,
3
+
2
923, 2852, 1596, 1511, 1482, 1452, 1440, 1287. HRMS (ESI) m/z calcd for C H N [M+H] 303.1856, found 303.1857.
21 22
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Synthesis of 2,4-diphenyl-6-(pyrrolidin-1-yl)pyridine (3ac)
Mes
Method A for the cycloaddition was used with iron iodide (2.6 mg, 0.00825 mmol), PDAI (7.0
mg, 0.0165 mmol), alkyne 1a (54.3 μL, 0.495 mmol), and cyanamide 2c (16.6 μL, 0.165 mmol).
The product was isolated by preparatory TLC (10% ethyl acetate in hexanes) in 87% (43.5 mg)
1
yield of pyridine 3ac as a yellow oil. H NMR (400 MHz, CDCl ) δ 8.15-8.06 (m, 2H), 7.72-7.64
3
1
3
(
m, 2H), 7.54-7.33 (m, 6H) 7.24 (d, J = 1.0 Hz, 1H), 6.51 (s, 1H), 3.63 (t, J = 6.5 Hz, 4H), 2.06 (t, J = 6.5 Hz, 4H). C (101
-1
MHz, CDCl ) δ 157.7, 155.9, 150.3, 140.3 (2C), 128.8, 128.41, 128.39, 128.36, 127.1, 126.9, 106.9, 103.0, 46.8, 25.6. IR (cm )
3
+
3
060, 2925, 2855, 1605, 1542, 1453, 1385, 1271. HRMS (ESI) m/z calcd for C H N [M+H] 301.1699, found 301.1698.
21
20
2
1D NOESY Relationships
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2
Synthesis of 2,4-diphenyl-6-(piperidin-1-yl)pyridine (3ad)
Mes
Method A for the cycloaddition was used with iron iodide (3.4 mg, 0.0079 mmol), PDAI (5.8
mg, 0.0159 mmol), alkyne 1a (52.3 μL, 0.477 mmol), and cyanamide 2d (18.4 μL, 0.159 mmol).
The product was isolatd by preparatory TLC (5% ethyl acetate in hexanes, Rf = 0.6) in 83% (41.5
1
mg) yield of pyridine 3ad as a yellow oil. H NMR (400 MHz, CDCl ) δ 8.09 (dt, J = 8.3, 1.8 Hz,
3
13
2
H), 7.71-7.62 (m, 2H), 7.53-7.34 (m, 6H), 7.37 (s, 1H), 6.80 (s, 1H) 3.71 (t, J = 5.6 Hz, 4H), 1.74-1.68 (m, 6H). C (101 MHz,
-
1
CDCl ) δ 159.9, 155.7, 140.3, 140.2, 128.8, 128.5, 128.4, 127.1, 126.9 (2C), 108.1, 103.8, 46.4, 25.6, 24.9. IR (cm ) 3060, 2931,
3
+
2852, 1595, 1545, 1495, 1447, 1243. HRMS (ESI) cacld for C H N [M+H] 315.1856, found 315.1856.
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Synthesis of 4-(4,6-diphenylpyridin-2-yl)morpholine (3ae)
Mes
Method A for the cycloaddition was used with iron iodide(2.4 mg, 0.0079 mmol), PDAI (5.8
mg, 0.0158 mmol), alkyne 1a (52.0 μL, 0.474 mmol) and cyanamide 2e (16.0 μL, 0.158 mmol).
The product was isolated by preparatory TLC (10% ethyl acetate in hexanes, Rf = 0.3) in 48%
1
(
24.0 mg) yield of pyridine 3ae as a yellow oil. H NMR (400 MHz, CDCl ) δ 8.08 (d, J = 7.4 Hz,
3
1
3
2
H), 7.66 (d, J = 7.2 Hz, 2H), 7.54-7.35 (m, 7H), 3.90 (t, J = 4.0 Hz, 4H) 3.69 (t, J = 4.0 Hz, 4H). C (101 MHz, CDCl ) δ
3
-
1
159.8, 155.8, 151.2, 139.9, 139.8, 128.9, 128.7, 128.6, 128.5, 127.1, 126.9, 109.4, 103.6, 66.9, 45.8. IR (cm ) 3061, 2961, 2921, 2852,
+
1595, 1546, 1497, 1447, 1425, 1238. HRMS (ESI) m/z calcd for C H N O [M+H] 317.1648, found 317.1649.
21
20
2
1D NOESY Relationships
Synthesis of N,N-diallyl-4,6-diphenylpyridin-2-amine (3af)
Mes
Method A for the cycloaddition was used with iron iodide (2.8 mg, 0.0090 mmol), PDAI (6.7
mg, 0.0180 mmol), alkyne 1a (59.3 μL, 0.540 mmol), and cyanamide 2f (24.4 μL, 0.180 mmol).
The product was isolated by preparatory TLC (5% ethyl acetate in hexanes, Rf = 0.6) in 32%
1
(
16.0 mg) yield of pyridine 3af as a yellow oil. H NMR (400 MHz, CDCl ) δ 8.10 (dd, J = 5.3, 3.3
3
Hz, 2H), 7.68-7.1 (m, 2H), 7.52-7.34 (m, 8H), 7.28 (d, J = 1.0 Hz, 1H) 6.62 (d, J = 1.0 Hz, 1H), 5.97
13
(
ddt, J = 17.1, 10.4, 5.3 Hz, 2H), 5.33-5.15 (m, 4H), 4.28 (d, 4.3 Hz, 4H). C (101 MHz, CDCl ) δ 158.2, 155.5, 150.7, 140.3,
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40.1, 134.4, 128.8, 128.5, 128.4, 127.1, 126.8 (2C), 116.2, 107.5, 102.9, 50.4. IR (cm ) 3061, 3034, 2979, 2922, 2853, 1596, 1546,
+
1
480, 1223. HRMS (ESI) m/z calcd for C H N [M+H] 327.1856, found 327.1851.
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Synthesis of N,N-dibenzyl-4,6-diphenylpyridin-2-amine (3ag)
Mes
Method A for the cycloaddition was used with iron iodide (2.8 mg, 0.0090 mmol), PDAI
(6.7 mg, 0.0180 mmol), alkyne 1a (59.3 μL, 0.540 mmol), and cyanamide 2g (40 mg, 0.180
mmol). The product was isolated by preparatory TLC (10% ethyl acetate in hexanes, Rf = 0.6)
N
N
1
in 78% (39.0 mg) yield of pyridine 3ag as a yellow-green solid. mp 106-108 °C; H NMR (400
MHz, CDCl ) δ 8.17-8.09 (m, 2H), 7.61-7.54 (m, 2H), 7.49-7.36 (m, 15H), 7.34-7.28 (m, 2H),
3
1
3
6
.68 (s, 1H), 4.99 (s, 4H). C (101 MHz, CDCl ) δ 158.8, 155.5, 151.0, 140.0, 139.9, 138.8, 128.8, 128.6, 128.4, 128.2, 128.1, 127.3,
3
-1
1
27.1, 126.9, 126.8, 107.9, 102.6, 51.1. IR (cm ) 3084, 3061, 3030, 2919, 2855, 1596, 1547, 1496, 1480, 1450, 1361, 1221. HRMS
+
(
ESI) m/z calcd for C H N [M+H] 427.2169, found 427.2171.
3
1
26
2
1D NOESY Relationships
15
Synthesis of N,N-dimethyl-4,6-dipropylpyridin-2-amine (3ga)
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Mes
Method B for the cycloaddition reaction was used with iron iodide (3.7 mg, 0.0121 mmol), PDAI
(
9 mg, 0.0242 mmol), alkyne 1g (49.5 mg, 0.726 mmol), and cyanamide 2a (17.0 mg, 0.242 mmol).
The crude product was isolated by preparatory TLC (5% ethyl acetate in hexanes, Rf = 0.4) in 55%
1
(27.5 mg) yield of pyridine 3ga as a yellow oil. H NMR (400 MHz, CDCl ) δ 6.26 (s, 1H), 6.15 (s,
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0
1
2
3
4
5
6
7
8
9
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H), 3.06 (s, 6H), 2.58 (t, J = 8 Hz, 2H), 2.46 (t, J = 8 Hz, 2H), 1.81-1.55 (m, 4H), 1.0-0.90 (m, 6H). C (101 MHz, CDCl ) δ
3
-
1
1
60.1, 159.5, 152.5, 111.2, 102.6, 40.4, 38.0, 37.9, 23.7, 22.6, 14.0, 13.9. IR (cm ) 2959, 2930, 2871, 1604, 1564, 1498, 1420, 1185.
+
HRMS (ESI) m/z calcd for C H N [M+H] 207.1856, found 207.1862.
1
3
22
2
1
D NOESY Relationships
15
Synthesis of 4,6-bis(((tert-butyldimethylsilyl)oxy)methyl)-N,N-dimethylpyridin-2-amine (3ha)
Method B for the cycloaddition reaction was used with iron iodide (2.8 mg, 0.00915 mmol),
Mes
PDAI (6.8 mg, 0.083 mmol), alkyne 1h (111.3 μL, 0.459 mmol), and cyanamide 2a (14.9 μL,
0.183 mmol). The crude product was purified by preparatory TLC (10% ethyl acetate in hexanes,
1
Rf = 0.6) in 83% (62.3 mg) yield of pyridine 3ha as a yellow oil. H NMR (400 MHz, CDCl ) δ 6.69 (s, 1H), 6.43 (s, 1H),
3
1
3
4
.68 (s, 4H), 3.07 (s, 6H), 0.96 (s, 9H), 0.97 (s, 9H), 0.12 (s, 6H), 0.11 (s, 6H). C (101 MHz, CDCl ) δ 159.1, 159.0, 104.9,
3
-
1
1
00.7, 66.3, 64.3, 38.1, 26.0, 25.9, 18.43, 18.37, -5.31 (2C). IR (cm ) 2955, 2929, 2857, 1610, 1569, 1501, 1471, 1421, 1391, 1255,
+
1
147, 1107. HRMS (ESI) m/z calcd for C H N O Si [M+H] 411.2858, found 411.2864.
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D NOESY Relationships
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Synthesis of 4,6-bis(2-((tert-butyldimethylsilyl)oxy)ethyl)-N,N-dimethylpyridin-2-amine (3ia)
Method B for the cycloaddition reaction was used with iron iodide (2.6 mg, 0.00855 mmol),
Mes
PDAI (6.3 mg, 0.0171 mmol), alkyne 1i (105.9 μL, 0.513 mmol), and cyanamide 2a (13.9 μL,
0
.171 mmol). The crude product was purified by preparatory TLC (10 % Ethyl acetate in
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hexanes, Rf = 0.6) in 69% (51.8 mg) yield of pyridine 3ia as a yellow oil. H NMR (300 MHz,
CDCl ) δ 6.32 (s, 1H), 6.20 (s, 1H), 3.96 (t, J = 7.1 Hz, 2H), 3.78 (t, J = 7.0 Hz, 2H), 3.05 (s, 6H), 2.82 (t, J = 7.1 Hz, 2H), 2.69
3
13
(
t, J = 7.0 Hz, 2H), 0.88 (s, 9H), 0.87 (s, 9H), 0.01 (s, 6H), 0.00 (s, 6H). C (101 MHz, CDCl ) δ 159.4, 156.9, 149.1, 112.6,
3
-1
1
03.8, 63.7, 63.2, 41.8, 39.4, 38.0, 26.0, 25.9, 18.33, 18.29, -5.33,
-5.37. IR (cm ) 2955, 2930, 2886, 2858, 1607, 1564, 1472,
+
1
421, 1389, 1255, 1099. HRMS (ESI) m/z calcd for C H N O Si [M+H] 439.3171, found 439.3175.
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46
2
2
2
1D NOESY Relationships
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Synthesis of N,N-dimethyl-4,6-diphenethylpyridin-2-amine (3ja)
Mes
Method B was for the cycloaddition was used with iron iodide (2.3 mg, 0.0076 mmol), PDAI
(
5.6 mg, 0.0151 mmol), alkyne 1j (63.7 μL, 0.453 mmol), and cyanamide 2a (12.3 μL, 0.151 mmol).
The crude product was purified by preparatory TLC (10 % ethyl acetate in hexanes, Rf = 0.6) in
1
59% (29.5 mg) yield of pyridine 3ja as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.35-7.2 (m,
3
1
3
10H), 6.29 (s, 1H), 6.16 (s, 1H), 3.10-3.07 (m, 8H), 2.89-2.98 (m, 4H), 2.81 (dd, J = 10.0, 6.2 Hz, 2H). C (101 MHz, CDCl ) δ
3
-
1
1
59.5, 159.2, 151.7, 142.5, 141.5, 128.5, 128.4, 128.3, 128.2, 125.9, 125.6, 111.1, 102.9, 40.0, 38.0, 37.7, 36.9, 35.5. IR (cm ) 3084,
+
3
062, 3026, 2924, 2857, 1603, 1563, 1496, 1454, 140, 1192. HRMS (ESI) m/z cacld for C H N [M+H] 331.2169, found
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31.2174.
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D NOESY Relationships
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Synthesis of N,N-dimethyl-4,6-bis(trimethylsilyl)pyridin-2-amine (3ka)
Mes
Method B for the cycloaddition was used with iron iodide (2.9 mg, 0.0094 mmol), PDAI (6.9 mg,
0.0188 mmol), alkyne 1k (79.7 μL, 0.564 mmol), and cyanamide 2a (15.3 μL, 0.188 mmol). The crude
product was purified by preparatory TLC (10% ethyl acetate in hexanes, Rf = 0.5) in 60% (30.0 mg)
1
yield of pyridine 3ka as a yellow oil. H NMR (400 MHz, CDCl ) δ 6.88 (s, 1H), 6.57 (s, 1H), 3.11 (s, 6H), 0.29 (s, 9H), 0.27
3
1
3
-1
(
s, 9H). C (101 MHz, CDCl ) δ 164.1, 157.9, 148.0, 121.0, 109.5, 37.8, -1.5, -1.7. IR (cm ) 2956, 2898, 2855, 2802, 1574, 1520,
3
+
1
486, 1396, 1334, 1248, 1184. HRMS (ESI) m/z calcd for C H N Si [M+H] 267.1707, found 267.1712.
1
3
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2
2
1D NOESY Relationships
H
H
H
Si
N
N
H
H
Si
15
Synthesis of 4,6-dicyclopropyl-N,N-dimethylpyridin-2-amine (3la)
Mes
Method B for the cycloaddition was used with iron iodide (3.9 mg, 0.0124 mmol), PDAI (9.1 mg,
0.247 mmol), alkyne 1l (62.7 μL, 0.741 mmol), and cyanamide 2a (20.1 μL, 0.247 mmol). The crude
product was purified by preparatory TLC (10% ethyl acetate in hexanes, Rf = 0.6) in 54% (27.0 mg)
1
yield of pyridine 3la as a yellow oil. H NMR (400 MHz, CDCl ) δ 6.13 (s, 1H), 6.02 (s, 1H), 3.01 (s, 6H), 1.88-1.79 (m, 1H),
3
1
3
1
.79-1.71 (m, 1H), 1.04-0.91 (m, 4H), 0.85-0.78 (m, 2H), 0.78-0.72 (m, 2H). C (101 MHz, CDCl ) δ 160.3, 159.4, 154.2, 106.3,
3
-
1
99.6, 37.8, 16.9, 15.3, 9.3, 8.7. IR (cm ) 3085, 3005, 2927, 2856, 2801, 1603, 1561, 1498, 1422, 1400, 1177. HRMS (ESI) m/z
+
calcd for C H N [M+H] 203.1543, found 203.1551.
13
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Synthesis of N,N-dimethyl-4,6-di(thiophen-3-yl)pyridin-2-amine (3ma)
Mes
Method B for the cycloaddition was used with iron iodide (2.7 mg, 0.00875 mmol), PDAI (6.5
mg, 0.0175 mmol), alkyne 1m (51.7 μL, 0.525 mmol), and cyanamide 2a (14.2 μL, 0.175 mmol). The
produced was isolated by preparatory TLC (10% ethyl acetate in hexanes, Rf = 0.5) in 69% (34.5 mg)
1
yield of pyridine 3ma as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.93 (dd, J = 3.0, 0.9 Hz, 1H), 7.71
3
(
dd, J = 5.0, 0.8 Hz, 1H), 7.71 (dd, J = 5.0, 0.8 Hz, 1H), 7.62 (dd, J = 2.8, 1.2 Hz, 1H) 7.50-7.33 (m, 3H), 7.13 (s, 1H), 6.61 (s,
1
3
1
H), 3.20 (s, 6H). C (101 MHz, CDCl ) δ 159.6, 151.9, 144.7, 143.2, 141.3, 126.40, 126.35, 126.2, 125.6, 122.9, 122.1, 106.4, 101.3,
3
-
1
+
38.0. IR (cm ) 3102, 2924, 2852, 2801, 1603, 1554, 1526, 1418, 1186, 1173. HRMS (ESI) m/z calcd for C H N S [M+H]
1
5
14
2 2
287.0671, found 287.0677.
1D NOESY Relationships
Synthesis of 4,6-bis(4-((tert-butyldimethylsilyl)oxy)phenyl)-N-methyl-N-phenethylpyridin-2-amine(3nh)
Method A for the cycloaddition was used with iron iodide (1.2 mg, 0.0040 mmol),
Mes
PDAI (3.0 mg, 0.008 mmol), tert-butyl(4-ethynylphenoxy)dimethylsilane (55.8
mg, 0.240 mmol), and N-methyl-N-phenethylcyanamide (12.8 mg, 0.08 mmol). The
product was isolated by preparatory TLC (10% ethyl acetate in hexanes, Rf = 0.5) in
1
76% (38 mg) yield of pyridine 3nh as a yellow oil. H NMR (400 MHz, CDCl ) δ 7.94
3
(
(
d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.27-7.10 (m, 6H), 6.88-6.83 (m, 4H), 6.45 (s, 1H), 3.84 (t, J = 7.5 Hz, 2H), 3.03
1
3
s, 3H), 2.92 (t, J = 7.5 Hz, 2H), 0.95 (s, 18H), 0.18-0.17 (m, 12H). C (75 MHz, CDCl ) δ 158.4, 156.3, 156.2, 155.2, 150.2,
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40.2, 133.6, 133.4, 128.9, 128.4, 128.1, 128.0, 126.1, 120.3, 120.0, 106.2, 101.2, 52.6, 36.9, 33.8, 29.7, 25.72, 25.69, 18.3, 4.4 (2C).
-
1
+
IR (cm ) 2955, 2929, 2857, 1604, 1545, 1510, 1264, 1168. HRMS (ESI) m/z calcd for C H N O Si [M+H] 625.3640, found
3
8
52
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625.3646.
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D NOESY Relationships
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Synthesis of 4,4'-(6-(methyl(phenethyl)amino)pyridine-2,4-diyl)diphenol (5)
A 2 mL vial was charged with 4,6-bis(4-((tert-butyldimethylsilyl)oxy)phenyl)-N-methyl-N-
phenethylpyridin-2-amine (39 mg, 0.03 mmol), potassium hydroxide (10.6 mg, 0.189
mmol), and ethanol (0.5 mL) with a magnetic stir bar. The reaction was monitored stirred
for 4 hours and filtered through Celite. Solvent was removed in vacuo and the crude
product was purified by preparatory TLC (50% ethyl acetate in hexanes, Rf = 0.5) to give
1
9
2% (35.9 mg) yield of deprotected pyridine 5 as a green oil. H NMR (400 MHz, CDCl ) δ 8.13 (d, J = 8.5 Hz, 2H), 7.66
3
13
(
(
5
d, J = 8.5Hz, 2H), 7.45-7.30 (m,6H), 7.06-6.99 (m, 4H) 6.63 (s, 1H), 4.02 (t, J = 8 Hz), 3.22 (s, 3H), 3.10 (t, J = 8 Hz).
C
101 MHz, CDCl ) δ 158.5, 156.1, 156.0, 155.2, 150.1, 140.1, 133.1, 133.0, 128.9, 128.5, 128.4, 128.3, 126.1, 115.7, 115.3, 106.1, 101.2,
3
-
1
2.6, 36.9, 33.8. IR (cm ) 3368 (br), 3084, 3064, 3026, 2928, 1603, 1545, 1513, 1453, 1233, 1172. HRMS (ESI) m/z cald for
+
C H N O [M+H] 397.1916, found 397.1918.
26
24
2
2
Associated Content
Supporting Information
This material is available free of charge via the Internet at http://pubs.acs.org. Experimental details, characterization
data, x-ray crystallographic data, and spectra.
Author Information
Corresponding Author
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louie@chem.utah.edu
Notes
The authors declare no competing financial interests.
Acknowledgment
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We gratefully acknowledge the National Institute of Health (GM076125) for financial support. We also thank Dr. Jim
Muller and Dr. Atta R. Arif of the University of Utah for providing HRMS and for X-ray analysis of compound 4,
respectively.
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(
(
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