Iron-catalyzed formation of 2-aminopyridines from diynes and cyanamides

Article abstract of DOI:10.1021/jo3012418

Diynes and cyanamides undergo an iron-catalyzed [2 + 2 + 2] cycloaddition to form highly substituted 2-aminopyridines in an atom-efficient manner that is both high yielding and regioselective. This system was also used to cyclize two terminal alkynes and

Full text of DOI:10.1021/jo3012418

Article
pubs.acs.org/joc
Iron-Catalyzed Formation of 2‑Aminopyridines from Diynes and
Cyanamides
Timothy K. Lane, Brendan R. D’Souza, and Janis Louie*
Henry Eyring Building, Department of Chemistry, University of Utah, 315 S 1400 E, Salt Lake City, Utah 84112-0850, United States
S
* Supporting Information
ABSTRACT: Diynes and cyanamides undergo an iron-catalyzed [2 + 2 + 2] cycloaddition to form highly substituted
2-aminopyridines in an atom-efficient manner that is both high yielding and regioselective. This system was also used to cyclize
two terminal alkynes and a cyanamide to afford a 2,4,6-trisubstituted pyridine product regioselectively.
relatively high catalyst loadings were required in both systems.
In addition, these systems either gave pyridines in moderate
yields (former) or required 10−20 molar equivalents of nitrile
(latter).6 Although these reports are an important step forward,
an efficacious iron-catalyzed route to pyridines that utilizes
low catalyst loading yet affords high yield of pyridine remains
scarce.
Attempts to react unactivated nitriles with diynes using our
system afforded only traces of pyridine products. Reactions
with electron deficient nitriles were also unsuccessful. Our
recent work with cyanamides suggested that they could be
suitable partners in Fe-catalyzed cycloaddition chemistry as
they appeared to be more reactive in Ni-catalyzed cyclo-
additions.7 Thus, 2-aminopyridines could potentially be
prepared by our iron bisiminopyridine catalyst without requir-
ing a large excess of cyanamide or having to tether the
cyanamide to an alkyne.
INTRODUCTION
■
The introduction of complex substitution patterns onto pyri-
dine rings can require multiple synthetic steps. Alternatively,
metal catalyzed [2 + 2 + 2] cycloadditions can create highly
substituted pyridines in a single step from simple starting
materials.1 This remarkably powerful method allows for the
efficient and regioselective construction of pyridines in addition
to bi- and tricyclic-fused pyridine ring systems. Despite the
abundance and low cost of iron salts, only a few examples of
iron-catalyzed pyridine formation exist.2
We recently developed the first general iron-catalyzed
method for pyridine synthesis.3 In our initial report, the strong
tendency for iron to cyclotrimerize alkynes was overcome using
alkynenitrile substrates along with a unique bis(aldimino)-
pyridine ligand (L1) (eq 1).4 Shortly after our initial report,
Variations on the 2-aminopyridine core have been studied
extensively due to their potential as medicinally useful
compounds.8 2-Aminopyridines are also a central structural
motif in α-carboline natural products9 as well as in a variety
chromophores,10 pharmacophores,11 OLED’s,12 and inorganic
ligands.13 These broadly applicable compounds are commonly
synthesized by Buchwald-Hartwig type aminations,14 nucleo-
philic aromatic substitutions,15 and multicomponent condensa-
tions.16 Such methods are useful for the creation of simple
2-aminopyridines, but more complex substitution patterns
require additional synthetic manipulations. For more complex
Wan and co-workers published an iron-catalyzed synthesis of
pyridines from diynes and nitriles (eq 2).5 Unfortunately,
Received: June 28, 2012
Published: July 28, 2012
© 2012 American Chemical Society
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aminopyridines, Co, Ni, Rh, and Ti catalysts and a photo-
catalytic system have all been used to mediate [2 + 2 + 2]
cycloadditions.17 However, in most of these studies (i.e., Ni,
Rh, and Ti), only a single example of a [2 + 2 + 2] cyclo-
addition with a cyanamide was demonstrated. In an effort to
improve the conditions and expand the scope of these
reactions, we recently developed a Ni/NHC-catalyzed system
for the [2 + 2 + 2] formation of 2-aminopyridines from diynes
and cyanamides.7 Although this system was high yielding and
regioselective, the low cost and environmentally benign nature
of iron compares favorably to nickel. Additionally we felt that
highly reactive cyanamides presented an opportunity to
improve on iron-catalyzed pyridine formation. Herein, we
report the successful development of an iron catalyst for the
cycloaddition of diynes and cyanamides to afford 2-amino-
pyridines.
diyne 1b both afforded products (3a and 3b) in excellent yield
(entries 1−2). The challenging terminal diyne 1c provided 3c
in good yield (entry 3). However, other difficult substrates such
as phenyl and TMS substituted diynes (1d and 1e respectively,
entries 4−5) were unreactive. The lack of Thorpe-Ingold effect
in substrates 1f and 1g did not effect cycloaddition as products
3f and 3g were both obtained in 84% yield (entries 6−7).
Notably, entries 1 and 6 demonstrate that heteroatom tethers,
which were problematic in the previous iron systems,3,5 are well
tolerated by this system. Diyne 1h successfully provided the
6,6-bicyclic pyridine (3h) in good yield (entry 8). High yields
of 2-aminopyridine were obtained with methyl-phenyl (2d)
and dimethyl (2b) substituted cyanamides substrates (entries 9
and 11). Surprisingly, cycloaddition of diethyl cyanamide 2c
afforded a lower yield of product (entry 10). Cyclic cyanamides
N-cyanopiperidine (2e) and N-cyanomorpholine (2f) reacted
readily (entries 12−13). Despite the apparent negative effect of
cyanamide sterics in entry 10, the large dibenzazepinyl cyana-
mide provided 3n in good yield (entry 14). This result com-
pares well with the 19% yield afforded by cobalt.17c Attempts to
react (dimethylamino)acetonitrile with diyne 1b were un-
successful, which may indicate that the inherent electronic
structure of cyanamides, not a chelation effect, is the source of
their high reactivity in this system.21 To demonstrate the
synthetic utility of this methodology, entry 1 was repeated on a
1 mmol scale leading to a comparable yield of 94% (eq 5).
RESULTS AND DISCUSSION
■
We were delighted when our first attempt to make 2-amino-
pyridine 3a from diyne 1a and 2 equivalents of cyanamide 2a
using our original catalyst system (10 mol % Fe(OAc)2, 13 mol
% Zn and 13 mol % L1 in DMF) afforded 2-aminopyridine 3a
in 69% isolated yield at 85 °C (eq 3). Furthermore, the use of a
simpler ligand (L2) led to an increase in isolated yield (85%).18
Further optimization led to conditions employing 5 mol %
catalyst loading of inexpensive FeCl2, 10 mol % Zn and 10 mol %
L2 in benzene over 4 h at room temperature. Evaluation of
other ligands (N-heterocyclic carbenes, phosphines, and pyridyl
diimines) provided no product.19
Unfortunately, the mild conditions that worked for the
model substrates (i.e., 1a and 2a) were not amenable to other
diynes. Although increasing the reaction temperature to 70 °C
led to good reactivity of the substrates, diyne dimerization
accounted for as much as half of substrate conversion. An
excess of cyanamide (10 equiv) led to no reactivity suggest-
ing that cyanamide binding out-competes alkyne binding at
high concentrations. Gratifyingly, slow addition of diyne over
the course of 3 h solved this problem and provided a general
method for coupling a variety of diynes. Slow addition of the
diyne also allowed us to decrease the cyanamide:diyne ratio to
1.2:1 with no deleterious effects on the yield.
Control studies to establish the necessity of iron for the
reaction were carried out. Importantly, removing any part of the
catalytic system renders the reaction ineffective. Additionally,
(L2)FeBr2 was independently synthesized and used directly
as an all-in-one catalyst precursor to provide a 97% NMR
yield (eq 4). That is, the combination of (L2)FeBr2 and Zn
dust provided a catalytically competent system. No reaction
occurred in the absence of zinc dust.20
For future synthetic application, an understanding of regio-
selectivity of unsymmetrical coupling partners is paramount.
Diynes 1i−k were evaluated under our optimized conditions
and the results are summarized in Table 2. In each of these
cases, good yields of 2-aminopyridine products were obtained.
What is surprising, however, is that each of the reactions shows
a strong preference to place the larger substituent proximal to
the pyridine nitrogen. For example, the cycloaddition of H, Me
substituted diyne 1i and cyanamide 2b provided an 85:15 ratio
of 3o and 3o′ in 72% combined yield (entry 1). A similar
product ratio was obtained in the cycloaddition of a bulkier
diyne (1j, entry 2) as well as aryl/alkyl diyne (1k, entry 3).
These regioselectivity trends provide an alternative to nickel-
catalyzed systems where the larger substituent is placed at the
3-position of the 2-aminopyridine ring.7 Additionally, this Fe-
catalyzed method is milder than the cobalt-catalyzed system
which is primarily limited to terminal alkynes.17c Notably, the
regioselectivity is the reverse of that observed in the previ-
ous Fe-catalyzed system involving diynes and nitriles wherein
the larger alkyne substituent was placed ortho to the nitrile
A broad range of diynes and cyanamides were successfully
converted to their respective 2-aminopyridines (Table 1). The
protected nitrogen backbone diyne 1a and malonate backbone
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a b
,
Table 1. Fe-Catalyzed Cycloaddition of Diynes and Cyanamides
a
b
5 mol % FeCl2, 10 mol % L2, 10 mol % Zn dust, diyne (0.4 M), cyanamide (0.48 M), benzene, 70 °C. 3 h slow addition of diyne unless otherwise
c
d
e
f
noted. Ts = p-toluenesulfonyl. TMS = trimethylsilyl. 5 h slow addition of substrate. 10 mol % FeCl2, 20 mol % L2, 20 mol % Zn dust.
Table 2. Unsymmetrical Diynes
a
b
oligomerization to provide unwanted side products.1,23 Despite
this potential pitfall, as well as the possibility of forming multi-
ple regioisomers, we found that the reaction of 2 equivalents of
alkyne 4a and 1 equivalent of cyanamide 2b afforded 5a as a
single regioisomer in 90% yield (eq 4). This mild and efficient
route to 2-amino-4,6-aryl pyridines may provide an alternative
to multistep syntheses of biologically active compounds24 and is
the topic of further investigation in our lab.
entry
substrate
product
yield (3:3′)
1
2
3
1i, RS = H, RL = Me
3o
3p
3q
72 (85:15)
80 (86:14)
t
1j, RS = Me, RL = Bu
1k, RS = Me, RL = Ph
67 (88:12)
a
b
Yields reported as a combination of both regioisomers. Product
1
ratios determined by H NMR.
substituent.5 To verify that this trend is a result of the catalyst
and not the type of nitrile, we reacted diyne 1k with dimethyl
cyanamide 2b under the catalyst developed by Wan and co-
workers (eq 6). The FeI2/dppp system provided the product in
a 63% combined yield but with 3q′ as the major regioisomer in
a 10:90 (3q, 3q′) ratio, the opposite selectivity of our system.
The fully intermolecular [2 + 2 + 2] cycloaddition of alkynes
and nitriles to form pyridines is a challenging reaction. To date,
intermolecular reactions with cyanamides are limited to cobalt
catalysts, and these systems provide a mixture of products when
using unsymmetrical internal alkynes.22 Furthermore, no
reports of [2 + 2 + 2] cycloadditions involving aryl acetylenes
and cyanamides exist. Terminal aryl acetylenes are particularly
challenging substrates since these tend to undergo rapid
The contrast in regioselectivity between our FeCl2/L2
system and the FeI2/dppp system is the first example of
ligand-dependent regioselectivity in metal-catalyzed [2 + 2 + 2]
pyridine formation. The regioselectivity observed in our Fe
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Scheme 1. Proposed Mechanism
1H and 13C nuclear magnetic resonance spectra of pure compounds
were acquired at 400 and 100 MHz, unless otherwise noted. All
spectra are referenced to a singlet at 7.27 ppm for 1H and to the center
line of a triplet at 77.23 ppm for 13C. The abbreviations s, d, dd, dt, dq,
td, t, q, and quint stand for singlet, doublet, doublet of doublets,
doublet of triplets, doublet of quartets, triplet of doublets, triplet,
quartet, and quintet, respectively. All 13C NMR spectra were proton
decoupled. Gas Chromatography was performed using the following
conditions: initial oven temperature: 100 °C; temperature ramp rate
10 °C/min.; final temperature: 300 °C held for 12 min; detector
temperature: 250 °C.
General Procedure for the Cycloaddition. In a nitrogen filled
glovebox, 5 mol % FeCl2, 10 mol % L2 and benzene was added to a
vial. The mixture was stirred for 10 to 15 min at which time 1.2
equivalents of cyanamide 2 (2.7 M in benzene) and 10 mol % Zn dust
was added. The vial was then capped with a Teflon lined septum screw
cap and removed from the glovebox. The vial was stirred in a 70 °C oil
bath and a solution of diyne 1 (0.49 M in benzene) was slowly added
to the vial over 3 h (unless otherwise noted) via syringe pump. (The
final concentration of the diyne after addition was 0.4 M.)
Purification Procedure A. For 2-aminopyridines with an Rf > 0.3
(20% ethyl acetate in hexanes) L2 (Rf = 0.51, 20% ethyl acetate in
hexanes) may coelute with and contaminate the final product. This
method was devised to avoid this issue. Once the reaction was
complete, as determined by GC, the crude mixture was stirred in
aqueous HCl for 10 min to protonate the 2-aminopyridine product.
The aqueous layer was collected and the organic layer was further
extracted with 4 × 15 mL portions of aqueous HCl. The aqueous
extracts were collected then a saturated aqueous NaHCO3 solution
was carefully added until the pH was >7, causing the product to
precipitate. The aqueous layer was then extracted with 3 × 25 mL
portions of diethyl ether. The organic extracts were collected, dried
over Na2SO4, filtered and the solvent was removed in vacuo. The crude
product was then purified via silica gel flash chromatography.
Purification Procedure B. For 2-aminopyridines with Rf < 0.3 (20%
ethyl acetate in hexanes). Once the reaction was complete, as
determined by GC, the crude mixture was purified via flash silica gel
chromatography. The product often contained unreacted cyanamide at
this point so the product was stirred in aqueous HCl for 10 min. The
aqueous layer was collected and the organic layer was further extracted
with 4 × 15 mL portions of aqueous HCl. The aqueous extracts were
collected then a saturated aqueous NaHCO3 solution was carefully
added until the pH was >7, causing the product to precipitate. The
aqueous layer was then extracted with 3 × 25 mL portions of diethyl
ether. The organic extracts were collected, dried over Na2SO4, filtered
and the solvent was removed in vacuo.
system mirrors that observed in Co-catalyzed protocols. As
such, this suggests that the L2/Fe-catalyzed cycloaddition of
cyanamides follows a similar mechanism to that of the well-
established mechanism for Co-catalyzed pyridine formation.25
Following in situ ligand coordination and reduction by zinc, a
reduced Fe catalyst binds the diyne and facilitates oxidative
coupling of the two alkyne units to form a ferracyclopentadiene
(Scheme 1). Insertion of cyanamide and reductive elimination
subsequently afford the pyridine product. Interestingly, the
FeI2/dppp catalyst system, which follows the regioselectivity
patterns of nickel, has been proposed to undergo a mechanism
involving initial oxidative coupling between an alkyne and a
nitrile instead.5 This is in agreement with the proposed mech-
anism for nickel-catalyzed pyridine formation.26 The regio-
selectivity results of this study, combined with what is known
about cobalt and nickel systems, may indicate that iron is
capable of following either mechanistic pathway and is depen-
dent on ligand choice. Studies to gain further insight into the
mechanistic difference between these two Fe based systems are
currently underway.
CONCLUSIONS
■
The iron catalyzed [2 + 2 + 2] cycloaddition of alkynes and
cyanamides is a high yielding, atom efficient and regioselective
method to obtain 2-aminopyridines. Iron catalyzed pyridine
synthesis is no longer limited by alkynenitrile substrates or large
excesses of nitrile. We are continuing our efforts to expand this
chemistry to other nitrile substrates.
EXPERIMENTAL SECTION
■
General Experimental. All reactions were conducted under an
atmosphere of N2 using standard Schlenk techniques or in a N2 filled
glovebox unless otherwise noted. Benzene was dried over neutral
alumina under N2 using a Grubbs type solvent purification system.
Iron Chloride (99.95% purity) was purchased from Alfa Aesar. Diynes
1a,27 1b−c,28 1d,29 1e,30 1f,31 1g,32 1h,33 1i,34 and 1j−k35 were pre-
pared from known literature procedures. Liquid cyanamides were
degassed using three sequential freeze−pump−thaw cycles. Slow addi-
tion of diyne was performed using a syringe pump 22 from a
disposable 1 mL syringe with a 6 in. stainless steel 24 gauge needle.
The needle was dried overnight at 160 °C and was fitted to the syringe
while hot. The syringe/needle joint was then wrapped tightly with
Teflon tape.
Synthesis of 4,7-Dimethyl-6-(pyrrolidin-1-yl)-2-tosyl-2,3-dihydro-
1H-pyrrolo[3,4-c]pyridine (3a). Compound 3a was prepared using the
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general procedure with 2a (42 mg, 4.4 × 10−1 mmol), FeCl2 (2.3 mg,
1.8 × 10−2 mmol), L2 (13.4 mg, 3.6 × 10−2 mmol), and zinc (2.4 mg,
3.6 × 10−2 mmol) in 418 μL of benzene. Diyne 1a (100 mg, 3.6 ×
10−1 mmol), dissolved in 490 μL benzene was added over 3 h at
70 °C. The reaction was stirred an additional 1 h for a total reaction
time of 4 h. After the reaction was complete (reaction monitored by
GC), the product was isolated as described in Purification Procedure B
with silica gel flash chromatography using 10% ethyl acetate in hexanes
followed by an acid/base extraction with 3 M HCl to yield 3a
(126 mg, 93%) as a white solid. Rf = 0.19 (20% ethyl acetate in
chromatography using 5% ethyl acetate in hexanes (500 mL), then
10% ethyl acetate in hexanes (500 mL) to yield 3g (86 mg, 84%) as a
1
yellow oil. Rf = 0.49 (20% ethyl acetate in hexanes). H (300 MHz,
CDCl3): δ (ppm) 1.89−1.92 (m, 4H), 2.06, (quint, J = 7.4 Hz, 2H),
2.17 (s, 4H), 2.33 (s, 3H), 2.80 (t, J = 7.5 Hz, 4H), 3.44 (t, J = 6.5 Hz,
4H). 13C (75 MHz, CDCl3) δ (ppm) 154.5, 147.4, 129.1, 129.0, 114.3,
50.4, 32.3, 30.6, 25.6, 24.8, 22.0, 16.0. IR (cm−1): 2953, 2868, 1595,
1425, 1347, 1204, 1137, 1063, 938, 858, 756. HRMS (ESI) m/z calcd
for C14H21N2 [M + H]+ 217.1705, found 217.1709.
Synthesis of Tetraethyl-1,4-dimethyl-3-(pyrrolidin-1-yl)-
isoquinoline-6,6,7,7(5H,8H)-tetracarboxylate (3h). Compound 3h
was prepared using the general procedure with 2a (18 mg, 1.9 × 10−1
mmol), FeCl2 (1.0 mg, 0.8 × 10−2 mmol), L2 (5.8 mg, 1.5 × 10−2
mmol), and zinc (1.0 mg, 1.5 × 10−2 mmol) in 100 μL of benzene.
Diyne 1h (67 mg, 1.6 × 10−1 mmol) dissolved in 300 μL benzene was
added over 3 h at 70 °C. The reaction mixture was stirred an addi-
tional 3 h for a total reaction time of 6 h. After the reaction was
complete (reaction monitored by GC), the crude product was isolated
with only silica gel flash chromatography (no acid/base extraction)
using 10% ethyl acetate in hexanes (200 mL), then 15% ethyl acetate
in hexanes (400 mL) to yield 3h (65 mg, 80%) as a yellow oil. Rf =
0.19 (20% ethyl acetate in hexanes). 1H (400 MHz, CDCl3): δ (ppm)
1.23 (td, J1 = 3.2, J2 = 3.2, J3 = 3.2 Hz, 12H), 1.86−1.92 (m, 4H), 2.12
(s, 3H), 2.34 (s, 3H), 3.30 (s, 2H), 3.36 (m, 6H), 4.13−4.25 (m, 8H).
13C (100 MHz, CDCl3) δ (ppm) 170.2, 170.1, 157.9, 150.2, 141.7,
1
hexanes). H and 13C NMR spectral data was compared with known
literature values.7a
Synthesis of Dimethyl 1,4-Dimethyl-3-(pyrrolidin-1-yl)-5H-
cyclopenta[c]pyridine-6,6-(7H)-dicarboxylate (3b). Compound 3b
was prepared using the general procedure with 2a (49 mg, 5.1 × 10−1
mmol), FeCl2 (2.7 mg, 2.1 × 10−2 mmol), L2 (16 mg, 4.2 × 10−2
mmol), and zinc (2.8 mg, 4.2 × 10−2 mmol) in 560 μL of benzene.
Diyne 3b (100 mg, 4.2 × 10−1 mmol), dissolved in 498 μL benzene,
was added over 3 h at 70 °C. The reaction mixture was stirred for an
additional 3 h for a total reaction time of 6 h. After the reaction was
complete (reaction monitored by GC), the product was isolated as
described in Purification Procedure B with silica gel flash
chromatography using 20% ethyl acetate in hexanes followed by an
acid/base extraction with 1 M HCl to yield 3b (127 mg, 90%) as a
1
yellowish solid. Rf = 0.27 (20% ethyl acetate in hexanes). H and 13C
NMR spectral data was compared with known literature values.7a
Synthesis of Dimethyl 3-(Pyrrolidin-1-yl)-5H-cyclopenta[c]-
pyridine-6,6-(7H)-dicarboxylate (3c). Compound 3c was prepared
using the general procedure with 2a (55 mg, 5.7 × 10−1 mmol), FeCl2
(3.0 mg, 2.4 × 10−2 mmol), L2 (18 mg, 4.8 × 10−2 mmol), and zinc
(3.1 mg, 4.8 × 10−2 mmol) in 194 μL of benzene. Diyne 1c (99 mg,
4.8 × 10−1 mmol), dissolved in 1 mL benzene, was added over 3 h at
70 °C. The reaction was stirred at 70 °C for an additional 15 h for a
total reaction time of 18 h. After the reaction was complete (reaction
monitored by GC), the product was isolated as described in Puri-
fication Procedure B with silica gel flash chromatography using 2%
methanol in dichloromethane followed by an acid/base extraction with
1 M HCl to yield 3c (94 mg, 65%) as a white solid. Rf = 0.01 (20%
ethyl acetate in hexanes). 1H and 13C NMR spectral data was
compared with known literature values.7a
118.2, 115.8, 62.2, 62.0, 61.9, 57.4, 57.1, 50.4, 33.1, 31.8, 25.5, 22.3,
14.8, 13.9. IR (cm−1): 2981, 2937, 2871, 2361, 1735, 1571, 1429, 1367,
1326, 1270, 1241, 1202, 1096, 1052, 942, 864, 784, 703, 650, 614, 580.
HRMS (ESI) m/z calcd for C28H27N2O4 455.1971, found 455.1969.
Synthesis of Dimethyl 3-(Dimethylamino)-1,4-dimethyl-5H-
cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3i). Compound 3i
was prepared using the general procedure B with 2b (20 mg, 2.8 ×
10−1 mmol), FeCl2 (1.5 mg, 1.2 × 10−2 mmol), L2 (8.8 mg, 2.4 × 10−2
mmol), and zinc (1.6 mg, 2.4 × 10−2 mmol) in 103 μL of benzene.
Diyne 1b (56 mg, 2.4 × 10−1 mmol) dissolved in 489 μL benzene was
added over 3 h at 70 °C. The reaction mixture was stirred an
additional 2 h for a total reaction time of 5 h. After the reaction was
complete (reaction monitored by GC), the product was isolated as
described in Purification Procedure B with silica gel flash
chromatography using 5% ethyl acetate in hexanes (500 mL), then
10% ethyl acetate in hexanes (500 mL), then 20% ethyl acetate in
hexanes (500 mL) followed by an acid/base extraction with 1 M HCl
Synthesis of 4,7-Diethyl-6-(pyrrolidin-1-yl)-1,3-dihydrofuro[3,4-
c]pyridine (3f). Compound 3f was prepared using the general
procedure with 2a (36 mg, 3.8 × 10−1 mmol), FeCl2 (2.0 mg, 1.6 ×
10−2 mmol), L2 (12 mg, 3.2 × 10−2 mmol), and zinc (2.1 mg, 3.2 ×
10−2 mmol) in 292 μL of benzene. Diyne 1f (47 mg, 3.2 × 10−1
mmol), dissolved in 497 μL benzene, was added over 5 h at 70 °C.
The reaction was stirred an additional 1 h for a total reaction time of
6 h. After the reaction was complete (reaction monitored by GC), the
product was isolated as described in Purification Procedure A with
an acid/base extraction using 1 M HCl then silica gel flash
chromatography using 5% ethyl acetate in hexanes (500 mL), then
10% ethyl acetate in hexanes (500 mL) to yield 3f (65 mg, 84%) as a
1
to yield 3i (71 mg, 97%) as a yellow oil. Rf = 0.27. H and 13C NMR
spectral data was compared with known literature values.7a
Synthesis of Dimethyl-3-(diethylamino)-1,4-dimethyl-5H-
cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3j). Compound 3j
was prepared using the general procedure with 2c (22 mg, 2.8 ×
10−1 mmol), FeCl2 (1.5 mg, 1.2 × 10−2 mmol), L2 (8.8 mg, 2.4 × 10−2
mmol), and zinc (1.6 mg, 2.4 × 10−2 mmol) in 103 μL of benzene.
Diyne 1b (56 mg, 2.4 × 10−1 mmol) dissolved in 489 μL benzene was
added over 3 h at 70 °C. The reaction mixture was stirred an addi-
tional 2 h for a total reaction time of 5 h. After the reaction was
complete (reaction monitored by GC), the product was isolated as
described in Purification Procedure B with silica gel flash chro-
matography using 10% ethyl acetate in hexanes followed by an acid/
base extraction with 1 M HCl to yield 3j (28 mg, 35%) as a yellow oil.
1
yellow oil. Rf = 0.52 (20% ethyl acetate in hexanes). H (300 MHz,
CDCl3): δ (ppm) 1.14 (t, J = 7.7 Hz, 3H), 1.23 (t, J = 7.5 Hz, 3H),
1.93 (quint, J = 3.3 Hz, 4H), 2.51−2.60 (m, 4H), 3.52 (quint, J = 3.2
Hz, 4H), 5.05 (s, 4H). 13C (75 MHz, CDCl3) δ (ppm) 158.0, 150.3,
149.8, 122.9, 116.2, 72.8, 72.4, 50.3, 29.2, 25.8, 23.0, 13.8, 12.5. IR
(cm−1): 2966, 2932, 2869, 1761, 1600, 1428, 1381, 1343, 1311, 1228,
1143, 1053, 906, 783. HRMS (ESI) m/z calcd for C15H23N2O
[M + H]+ 247.1810, found 247.1814.
Synthesis of 1,4-Dimethyl-3-(pyrrolidin-1-yl)-6,7-dihydro-5H-
cyclopenta[c]pyridine (3g). Compound 3g was prepared using the
general procedure with 2a (55 mg, 5.7 × 10−1 mmol), FeCl2 (3.0 mg,
2.4 × 10−2 mmol), L2 (18 mg, 4.8 × 10−2 mmol), and zinc (3.1 mg,
4.8 × 10−2 mmol) in 429 μL of benzene. Diyne 1g (57 mg, 4.8 × 10−1
mmol), dissolved in 765 μL benzene, was added over 5 h at 70 °C.
The reaction was stirred an additional 2 h for a total reaction time of
7 h. After the reaction was complete (reaction monitored by GC), the
product was isolated as described in Purification Procedure A with
an acid/base extraction using 1 M HCl then silica gel flash
1
Rf = 0.27 (20% ethyl acetate in hexanes). H and 13C NMR spectral
data was compared with known literature values.7a
Synthesis of Dimethyl-1,4-dimethyl-3-(methyl(phenyl)amino)-
5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3k). Compound
3k was prepared using the general procedure with 2d (22 mg, 1.8 ×
10−1 mmol), FeCl2 (1.0 mg, 7.5 × 10−2 mmol), L2 (5.5 mg, 1.5 × 10−2
mmol), and zinc (1.0 mg, 1.5 × 10−2 mmol) in 65 μL of benzene.
Diyne 1b (35 mg, 1.5 × 10−1 mmol) dissolved in 310 μL benzene was
added over 3 h at 70 °C. The reaction mixture was stirred an addi-
tional 2 h for a total reaction time of 5 h. After the reaction was
complete (reaction monitored by GC), the product was isolated as
described in Purification Procedure B with silica gel flash chro-
matography using 5% ethyl acetate in hexanes (250 mL), then 10% ethyl
acetate in hexanes (250 mL), 20% ethyl acetate in hexanes (500 mL)
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followed by an acid/base extraction with 1 M HCl to yield 3k (39 mg,
1
70%) as a yellowish oil. Rf = 0.16 (20% ethyl acetate in hexanes). H
and 13C NMR spectral data was compared with known literature
values.7a
Synthesis of Dimethyl-1,4-dimethyl-3-(piperidin-1-yl)-5H-
cyclopenta[c]-pyridine-6,6-(7H)-dicarboxylate (3l). Compound 3l
was prepared using the general procedure with 2e (31 mg, 2.8 ×
10−1 mmol), FeCl2 (1.5 mg, 1.2 × 10−2 mmol), L2 (8.8 mg, 2.4 × 10−2
mmol), and zinc (1.6 mg, 2.4 × 10−2 mmol) in 121 μL of benzene.
Diyne 1b (56 mg, 2.4 × 10−1 mmol) dissolved in 471 μL benzene was
added over 3 h at 70 °C. The reaction mixture was stirred an
additional 2 h for a total reaction time of 5 h. After the reaction was
complete (reaction monitored by GC), the product was isolated as
described in Purification Procedure B with silica gel flash chro-
matography using 5% ethyl acetate in hexanes (250 mL), then 10%
ethyl acetate in hexanes (250 mL), and 20% ethyl acetate and hexanes
(250 mL) followed by an acid/base extraction with 1 M HCl to yield
3l (78 mg, 97%) as a yellowish oil. Rf = 0.27 (20% ethyl acetate in
time of 8 h. After the reaction was complete (reaction monitored by
GC), the product was isolated as described in Purification Procedure B
with silica gel flash chromatography using 20% ethyl acetate in hexanes
followed by an acid/base extraction with 3 M HCl to yield 3o and 3o′
(38 mg, 72%, 85:15) as a white solid. Rf = 0.11 (20% ethyl acetate in
1
hexanes). 3o: H (400 MHz, CDCl3): δ (ppm) 2.26 (s, 3H), 2.42
(s, 3H), 3.02 (s, 6H), 4.45 (s, 2H), 4.51 (s, 2H), 6.12 (s, 1H), 7.32 (d,
J = 8, 2H), 7.77 (d, J = 8, 2H). 13C (100 MHz, CDCl3) δ (ppm) 159.4,
150.6, 147.2, 143.9, 134.0, 130.0, 118.2, 96.4, 53.9, 51.9, 38.4, 22.3,
21.7. MP 176−178 °C. 2-D NOESY (500 MHz, CDCl3): Hb (6.12
ppm) correlates to Ha (4.51 ppm). Hc (2.56 ppm) shows no
correlation to Ha. IR (cm−1): 2918, 2849, 1614, 1579, 1503, 1408,
1342, 1309, 1159, 1099, 815, 669, 579, 543. HRMS (ESI) m/z calcd
for C17H22N3O2S [M + H]+ 332.1433, found 332.1433.
1
hexanes). H (400 MHz, CDCl3): δ (ppm) 1.58 (q, J = 7.2 Hz, 2H)
1.68 (quint, J = 6 Hz, 4H), 2.14 (s, 3H), 2.33 (s, 3H), 3.0 (t, J = 4.8
Hz, 4H), 3.48 (s, 2H), 3.50 (s, 2H), 3.77 (s, 6H). 13C (100 MHz,
CDCl3) δ (ppm) 172.3, 161.8, 150.2, 148.3, 127.6, 118.3, 59.7, 53.3,
51.7, 40.1, 38.9, 26.6, 24.9, 21.9, 14.5. IR (cm−1): 2930, 2851, 1738,
1586, 1432, 1371, 1266, 1199, 1163, 1114, 1062, 1028, 963, 858, 610.
HRMS (ESI) m/z calcd for C19H27N2O4 [M + H]+ 347.1971, found
347.1980.
Synthesis of 4-(Tert-butyl)-N,N,7-trimethyl-2-tosyl-2,3-dihydro-
1H-pyrrolo[3,4-c]pyridin-6-amine (3p). Compounds 3p and 3p′
Synthesis of Dimethyl-1,4-dimethyl-3-morpholino-5H-
cyclopenta[c]pyridine-6,6-(7H)-dicarboxylate (3m). Compound 3m
was prepared using the general procedure with 2f (48 mg, 4.7 × 10−1
mmol), FeCl2 (2.7 mg, 2.1 × 10−2 mmol), L2 (16 mg, 4.2 × 10−2
mmol), and zinc (2.8 mg, 4.2 × 10−2 mmol) in 200 μL of benzene.
Diyne 2b (50 mg, 2.1 × 10−1 mmol) dissolved in 400 μL benzene was
added over 3 h at 70 °C. The reaction mixture was stirred an addi-
tional 2 h for a total reaction time of 5 h. After the reaction was
complete (reaction monitored by GC), the product was isolated as
described in Purification Procedure A with an acid/base extraction
using 1 M HCl then silica gel flash chromatography using 20% ethyl
acetate in hexanes (200 mL), then 30% ethyl acetate in hexanes
(400 mL) to yield 3m (49 mg, 67%) as a yellowish oil. Rf = 0.38 (20%
ethyl acetate in hexanes). 1H and 13C NMR spectral data was
compared with known literature values.7a
were prepared using the general procedure with 2b (13 mg, 1.9 ×
10−1 mmol), FeCl2 (1.0 mg, 7.9 × 10−2 mmol), L2 (5.8 mg, 1.6 × 10−2
mmol), and zinc (1.0 mg, 1.6 × 10−2 mmol) in 59 μL of benzene.
Diyne 1j (50 mg, 1.6 × 10−1 mmol), dissolved in 336 μL benzene was
added over 3 h at 70 °C. The reaction was stirred an additional 3 h for
a total reaction time of 6 h. After the reaction was complete (reaction
monitored by GC), the product was isolated as described in
Purification Procedure B with silica gel flash chromatography using
10% ethyl acetate in hexanes followed by an acid/base extraction with
3 M HCl to yield 3p and 3p′ (49 mg, 80%, 88:12) as a white solid.
Rf = 0.27 (20% ethyl acetate in hexanes). 3p: 1H (500 MHz, CDCl3):
δ (ppm) 1.29 (s, 9H), 2.10 (s, 3H), 2.42 (s, 3H), 2.79 (s, 6H), 4.24 (s,
2H), 2.74 (s, 2H), 7.34 (d, J = 8 Hz, 2H), 7.80 (d, J = 8 Hz, 2H). 13C
(125 MHz, CDCl3) δ (ppm) 160.2, 157.6, 148.0, 143.9, 134.0, 123.1,
127.8, 121.0, 114.6, 53.6, 52.3, 42.3, 38.6, 29.5, 21.7, 14.9. MP 101−
102 °C. 2-D NOESY (800 MHz, CDCl3): Ha (2.84 ppm) correlates to
Hb (2.09 ppm). Hc (1.28 ppm) does not correlate to Ha. HMBC (800
MHz, CDCl3): C1 (161.1 ppm) couples with Ha (2.84 ppm) and Hb
(2.09 ppm). IR (cm−1): 3633, 2954, 2866, 2792, 2361, 1726, 1599,
1566, 1478, 1453, 1416, 1392, 1351, 1315, 1251, 1204, 1165, 1099,
1066, 955, 930, 816, 772, 737, 711, 665, 607, 570, 548, 513. HRMS
(ESI) m/z calcd for C21H30N3O2S [M + H]+ 388.2059, found
388.2069.
Synthesis of Dimethyl-3-(5H-dibenzo[b,f]azepin-5-yl)-1,4-di-
methyl-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3n). Com-
pound 3n was prepared using the general procedure with 2g (83 mg,
4.7 × 10−1 mmol), FeCl2 (2.68 mg, 2.1 × 10−2 mmol), L2 (15.6 mg,
4.2 × 10−2 mmol), and zinc (2.8 mg, 4.2 × 10−2 mmol) in 121 μL of
benzene. Diyne 1b (50 mg, 2.1 × 10−1 mmol) dissolved in 471 μL
benzene was added over 3 h at 70 °C. The reaction mixture was stirred
an additional 19 h for a total reaction time of 22 h. After the reaction
was complete (reaction monitored by GC), the product was isolated as
described in Purification Procedure B with silica gel flash chro-
matography using 10% ethyl acetate in hexanes followed by an acid/
base extraction with 1 M HCl to yield 3n (133 mg, 69%) as a red oil.
1
Rf = 0.29 (20% ethyl acetate in hexanes). H (400 MHz, CDCl3): δ
(ppm) 1.78 (s, 3H), 2.44 (s, 3H), 3.44 (s, 2H), 3.54 (s, 2H), 3.75
(s, 6H), 6.85 (s, 2H), 7.07 (dt, J = 7.2 Hz, 0.8 Hz, 2H), 7.16 (dd, J = 8
Hz, 1.6 Hz, 2H), 7.22 (dd, J = 8 Hz, 1.6 Hz, 2H), 7.71 (dd, J = 8 Hz,
0.8 Hz, 2H). 13C (100 MHz, CDCl3) δ (ppm) 172.2, 156.1, 151.7,
148.4, 148.1, 135.1, 132.4, 129.6, 128.8, 127.3, 124.7, 120.4, 59.8, 53.3,
40.3, 39.0, 22.1, 14.9. IR (cm−1): 3020, 2953, 2923, 2854, 2361, 1737,
1589, 1482, 1432, 1340, 1266, 1200, 1163, 1113, 1060, 950, 922,
865, 794, 767, 735, 662, 559. HRMS (ESI) m/z calcd for C28H27N2O4
[M + H]+ 455.1971, found 455.1982.
Synthesis of N,N,7-Trimethyl-4-phenyl-2-tosyl-2,3-dihydro-1H-
pyrrolo[3,4-c]pyridin-6-amine (3q). Compounds 3q and 3q′ were
Synthesis of N,N,4-Trimethyl-2-tosyl-2,3-dihydro-1H-pyrrolo[3,4-
c]pyridin-6-amine (3o). Compounds 3o and 3o′ were prepared using
the general procedure with 2b (13 mg, 1.9 × 10−1 mmol), FeCl2
(1.0 mg, 7.9 × 10−2 mmol), L2 (5.8 mg, 1.6 × 10−2 mmol), and zinc
(1.0 mg, 1.6 × 10−2 mmol) in 93 μL of benzene. Diyne 1i (41 mg,
1.6 × 10−1 mmol), dissolved in 303 μL benzene was added over 3 h at
70 °C. The reaction was stirred an additional 5 h for a total reaction
prepared using the general procedure with 2b (13 mg, 1.9 × 10−1
mmol), FeCl2 (1.0 mg, 7.9 × 10−2 mmol), L2 (5.8 mg, 1.6 × 10−2
mmol), and zinc (1.0 mg, 1.6 × 10−2 mmol) in 93 μL of benzene.
Diyne 1k (53 mg, 1.6 × 10−1 mmol), dissolved in 302 μL benzene was
added over 3 h at 70 °C. The reaction was stirred an additional 3 h for
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a total reaction time of 6 h. After the reaction was complete (reaction
monitored by GC), the product was isolated as described in
Purification Procedure B with silica gel flash chromatography using
10% ethyl acetate in hexanes followed by an acid/base extraction with
3 M HCl to yield 3q and 3q′ (43 mg, 67%, 86:14) as a white solid.
Rf = 0.14 (20% ethyl acetate in hexanes). 3q: 1H (400 MHz, CDCl3):
δ (ppm) 2.18 (s, 3H), 2.42 (s, 3H), 2.87 (s, 6H), 4.53 (s, 2H), 4.82
(s, 2H), 7.28−7.47 (m, 5H), 7.76 (dd, J = 6.5, 7.5 Hz, 4H). 13C (125
MHz, CDCl3) δ (ppm) 161.9, 148.2, 147.1, 144.0, 139.4, 134.0, 130.1,
128.8, 128.7, 127.9, 127.8, 122.5, 116.9, 53.7, 52.9, 42.2, 21.7, 15.3.
HMBC (800 MHz, CDCl3): C1 (165.2 ppm) couples with Ha (2.86
ppm) and Hb (2.17 ppm). MP 176−177 °C. IR (cm−1): 2924, 2854,
2361, 1733, 1595, 1491, 1458, 1400, 1349, 1161, 1098, 1065, 913, 816,
753, 703, 673, 614, 581, 548. HRMS (ESI) m/z calcd for
C23H26N3O2S [M + H]+ 408.1746, found 408.1752. A crystal of 3q′
suitable for X-ray analysis was grown by slow evaporation from an
ether solution (see Supporting Information).
vial cap. The reaction was stirred for 24 h at 80 °C then cooled to
room temperature, filtered through a silica gel plug and flushed with
150 mL of ethyl acetate. The resulting solution was reduced in vacuo
and purified via silica gel flash chromatography with 10% ethyl acetate
in hexanes to yield 4-(methoxy)-2,6-dimethylaniline (3.90 g, 51%) as
1
a blue solid. Rf = 0.12 (20% ethyl acetate in hexanes). H NMR (300
MHz, CDCl3): δ (ppm) 2.20 (s, 6H), 3.23 (s, 2H), 3.75 (s, 3H), 6.58
(s, 2H). 13C NMR (125 MHz, CDCl3): δ (ppm) 152.23, 134.61,
123.4, 114.1, 55.9, 18.2. MP 38−40 °C. IR (cm−1): 3449, 3371, 1923,
2835, 1604, 1490, 1378, 1328, 1300, 1243, 1192, 1150, 1064, 949, 854,
728, 599. HRMS (ESI) m/z calcd for C9H14NO [M + H]+ 152.1075,
found 152.1083.
Synthesis of 4-(Methoxy)-2,6-diisopropylaniline. 4-(Methoxy)-2,6-
diisopropylaniline was prepared using a similar literature procedure.37
Synthesis of N,N-Dimethyl-4,6-di-p-tolylpyridin-2-amine (5a).
Compound 5a was prepared using the general procedure with 2b
In a nitrogen glovebox, a 20 mL scintillation vial was filled with CuI
(91.9 mg, 0.48 mmol) 3,4,7,8-tetramethyl-1,10-phenanthroline (228
mg, 0.95 mmol), Cs2CO3 (5.58 g, 28.9 mmol), and 4-iodo-2,6-
diisopropyl aniline4a (2.93 g, 9.65 mmol). The vial was sealed with a
rubber septum, removed from the glovebox then evacuated and
backfilled with Argon three times. Toluene (5 mL) was added and the
mixture was stirred at 80 °C for 20 min. Methanol (869 mg, 28.9
mmol) was added and the rubber septum was quickly replaced with a
vial cap. The reaction was stirred for 24 h at 80 °C then cooled to
room temperature, filtered through a silica gel plug and flushed with
150 mL of ethyl acetate. The resulting solution was reduced in vacuo
and purified via silica gel flash chromatography with 10% ethyl acetate
in hexanes to yield 4-(methoxy)-2,6-diisopropylaniline (1.83 g, 91%)
as a blue oil. Rf = 0.28 (20% ethyl acetate in hexanes). 1H NMR (300
MHz, CDCl3): δ (ppm) 1.32 (d, J = 6.5 Hz, 12H), 3.01 (quint J = 7.5
Hz, 2H), 3.50 (s, 2H), 3.82 (s, 3H), 6.70 (s, 2H). 13C NMR (125
MHz, CDCl3): δ (ppm) 152.9, 134.4, 134.0, 108.8, 55.7, 28.3, 22.6. IR
(cm−1): 3459, 3382, 2961, 2871, 2832, 2361, 1600, 1466, 1435, 1383,
1348, 1311, 1242, 1219, 1172, 1123, 1103, 1042, 939, 865, 760, 669.
HRMS (ESI) m/z calcd for C13H22NO [M + H]+ 208.1701, found
208.1700.
(22 mg, 3.2 × 10−1 mmol), FeCl2 (2.0 mg, 1.6 × 10−2 mmol), L2
(11.7 mg, 3.2 × 10−2 mmol), and zinc (2.1 mg, 3.2 × 10−2 mmol) in
108 μL of benzene. 4-Ethynyltoluene (73 mg, 6.3 × 10−1 mmol),
dissolved in 287 μL benzene was added over 3 h at 50 °C. The
reaction was stirred an additional 2 h for a total reaction time of 5 h.
After the reaction was complete (reaction monitored by GC), the
product was isolated as described in Purification Procedure A with an
acid/base extraction using 1 M HCl then silica gel flash
chromatography using 5% ethyl acetate in hexanes (500 mL to yield
5a (86 mg, 90%) as a white solid. Rf = 0.57 (20% ethyl acetate in
hexanes). 1H NMR (500 MHz, CD2Cl2) δ (ppm) 2.41 (d, J = 4.0 Hz,
6H), 3.20 (s, 6H), 6.67 (s, 1H), 7.24 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H),
7.30 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 8.0 (d, J = 7.0 Hz,
2H) . 13C (125 MHz, CDCl3) δ (ppm) 159.9, 155.8, 150.7, 138.51,
138.48, 137.8, 137.7, 129.7, 129.3, 127.2, 127.0, 107.1, 102.2, 38.3,
21.5, 21.4. 2-D NOESY (800 MHz, CDCl3): Ha (3.24 ppm) correlates
with Hb (6.66 ppm). HMBC (800 MHz, CDCl3): C1 (159.6 ppm)
couples with Ha (3.24 ppm) and Hb (6.66 ppm). C2 (137.6 ppm)
couples with Hb (6.66 ppm) and Hc (7.30 ppm). MP 99−101 °C. IR
(cm−1): 3026, 2920, 1599, 1543, 1511, 1416, 1401, 1250, 1181, 1114,
986, 836, 807, 602, 559. HRMS (ESI) m/z calcd for C21H23N2
[M + H]+ 303.1861, found 303.1864.
Synthesis of (N,N′E,N,N′E)-N,N′-(Pyridine-2,6-diylbis-
(methanylylidene))bis(4-methoxy-2,6-dimethylaniline) (L3). L3 was
Ligand Synthesis. L1,3 L2,36 and L429 were synthesized according
to the literature methods.
prepared from the similar literature procedure36 with 4-methoxy-2,6-
methyl aniline (1.54 g, 10.2 mmol) and 2,6-pyridinedicarboxaldehyde
(673 mg, 4.98 mmol) and 10 drops of glacial acetic acid in 15 mL
100% ethanol. The reaction was stirred overnight at room temper-
ature. The mixture was then cooled to 0 °C, filtered and rinsed with
cold 100% ethanol to yield L3 (1.9 g, 95%) as a yellow solid. Rf = 0.37
(20% ethyl acetate in hexanes). 1H NMR (300 MHz, CDCl3): δ
(ppm) 2.21, (s, 12H), 3.81 (s, 6H), 6.67 (s, 4H), 7.97 (t, J = 7.8 Hz,
1H), 8.37−8.40 (m, 4H). 13C NMR (75 MHz, CDCl3): δ (ppm)
163.4, 156.4, 154.8, 143.9, 137.4, 128.8, 122.8, 113.7, 55.53, 19.0. MP
190−192 °C. IR (cm−1): 3044, 2924, 2863, 2300, 1608, 1545, 1518,
1491, 1459, 1421, 1388, 1263, 1226, 1157, 1034, 996, 948, 879, 818,
736, 638, 573, 516. HRMS (ESI) m/z calcd for C25H28N3O2 [M + H]+
402.2182, found 402.2189.
Synthesis of 4-(Methoxy)-2,6-dimethylaniline. 4-(Methoxy)-2,6-
dimethylaniline was prepared using a similar literature procedure.30 In
a nitrogen glovebox, a 20 mL scintillation vial was filled with CuI
(353.8 mg, 1.86 mmol) 3,4,7,8-tetramethyl-1,10-phenanthroline
(877.4 mg, 3.71 mmol), Cs2CO3 (21.5 g, 111.4 mmol), and 4-iodo-
2,6-dimethyl aniline4a (9.17 g, 37.1 mmol). The vial was sealed with a
rubber septum, removed from the glovebox then evacuated and
backfilled with Argon three times. Toluene (14 mL) was added and
the mixture was stirred at 80 °C for 20 min. Methanol (3.6 mg, 111.4
mmol) was added and the rubber septum was quickly replaced with a
Synthesis of (N,N′E,N,N′E)-N,N′-(Pyridine-2,6-diylbis-
(methanylylidene))bis(4-(benzyloxy)-2,6-diisopropylaniline)
(L5). L5 was prepared from the similar literature procedure36
with 4-methoxy-2,6-diisoproply aniline (807 mg, 3.89 mmol) and 2,
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B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830−2834.
(h) Leboeuf, D.; Gandon, V.; Malacria, M. Handbook of Cyclization
Reactions 2010, 1, 367−405. (i) Wang, C.; Wan, B. Chin. Sci. Bull.
2012, 57, 2338−2351. (j) Agenet, N.; Buisine, O.; Slowinski, F.;
Gandon, V.; Aubert, C.; Malacria, M. Org. React. 2007, 68, 1−302.
(2) (a) Schmidt, U.; Zenneck, U. J. Organomet. Chem. 1992, 440,
187−190. (b) Knoch, F.; Kremer, F.; Schmidt, U.; Zenneck, U.
́
Organometallics 1996, 15, 2713−2719. (c) Ferre, K.; Toupet, L.;
Guerchais, V. Organometallics 2002, 21, 2578−2580.
6-pyridinedicarboxaldehyde (263 mg, 1.95 mmol) and 5 drops of
glacial acetic acid in 5 mL 100% ethanol. The reaction was stirred over-
night at room temperature. The mixture was then cooled to 0 °C,
filtered and rinsed with cold 100% ethanol to yield L3 (891 mg, 89%)
(3) D’Souza, B., R.; Lane, T. K.; Louie, J. Org. Lett. 2011, 13, 2936−
2939.
(4) Selected examples of iron catalyzed alkyne cyclotrimerization:
(a) tom Dieck, H.; Diercks, R. Angew. Chem., Int. Ed. 1983, 22, 1138−
1146. (b) Breschi, C.; Piparo, L.; Pertici, P.; Caporusso, A. M.; Vitulli,
G. J. Organomet. Chem. 2000, 607, 57−63. (c) Saino, N.; Kogure, D.;
Okamoto, S. Org. Lett. 2005, 7, 3065−3067. (d) Saino, N.; Kogure, D.;
Kase, K.; Okamoto, S. J. Organomet. Chem. 2006, 691, 3129−3136.
(e) Liu, Y.; Yan, X.; Yang, N.; Xi, C. Catal. Commun. 2011, 12, 489−
492.
1
as a yellow solid. Rf = 0.61 (20% ethyl acetate in hexanes). H NMR
(500 MHz, CDCl3): δ (ppm) 1.20 (d, J = 6.7 Hz, 24H), 3.03 (quint,
J = 6.9 Hz, 4H), 3.85 (s, 6H), 6.74 (s, 4H), 7.99 (t, J = 7.8 Hz, 1H),
8.36−8.40 (m, 4H). 13C NMR (125 MHz, CDCl3): δ (ppm) 163.4,
157.0, 154.7, 142.1, 139.1, 137.5, 122.8, 108.8, 55.5, 28.4, 23.7. MP 181−
184 °C. IR (cm−1): 3046, 2961, 2871, 2836, 1638, 1601, 1582, 1462, 1383,
1327, 1289, 1238, 1198, 1169, 1125, 1107, 1076, 1039, 990, 942, 866, 763,
739, 625, 526. HRMS (ESI) m/z calcd for C33H44N3O2 [M + H]+
514.3434, found 5143.3441.
(5) Wang, C.; Li, X.; Wu, F.; Wan, B. Angew. Chem., Int. Ed. 2011, 50,
7162−7166.
(6) The large excess of nitrile presumably favors pyridine formation
over diyne dimerization.
Synthesis of (L2)FeBr2. Adapted from the literature procedure.19b In
a nitrogen filled glovebox, L2 (109 mg, 5.1 × 10−1 mmol), FeBr2 (111 mg,
(7) (a) Stolley, R. M.; Maczka, M. T.; Louie, J. Eur. J. Org. Chem.
2011, 3815−3824. (b) Kumar, P.; Prescher, S.; Louie, J. Angew. Chem.,
Int. Ed. 2011, 50, 10694−10698.
(8) (a) Kamal, A.; Reddy, J. S.; Ramaiah, M. J.; Dastagiri, D.;
Bharathi, E. V.; Sagar, M. V. P.; Pushpavalli, S. N. C. V. L; Ray, P.; Pal-
Bhadra, M. Med. Chem. Commun. 2010, 8, 355−360. (b) Hilton, S.;
Naud, S.; Caldwell, J. J.; Boxall, K.; Burns, S.; Anderson, V. E.; Antoni,
L.; Allen, C. E.; Pearl, L. H.; Oliver, A. W.; Aherne, G. W.; Garrett, M.
D.; Collins, I. Bioorg. Med. Chem. 2010, 18, 707−718. (c) Garcin, E.
D.; Arvai, A. S.; Rosenfeld, R. J.; Kroeger, M. D.; Crane, B. R.;
Andersson, G.; Andrews, G.; Hamley, P. J.; Mallinder, P. R.; Nicholls,
D. J.; St-Gallay, S. A.; Tinker, A. C.; Gensmantel, N. P.; Mete, A.;
Cheshire, D. R.; Connolly, S.; Stuehr, D. J.; Aberg, A.; Wallace, A. V.;
Tainer, J. A.; Getzoff, E. D. Nature Chem. Biol. 2008, 4, 700−707.
(d) Takahashi, Y.; Furukawa, K.; Ishibashi, M.; Kozutsumi, D.;
Ishiyama, H.; Kobayashi, J.; Ohizumi, Y. Eur. J. Pharmacol., Mol.
Pharmacol. Sect. 1995, 288, 285−293. (e) Peczyska-Czoch, W.;
Pognan, F.; Kaczmarek, L.; Boratynski, J. J. Med. Chem. 1994, 37,
3503−3510.
5.1 × 10−1 mmol), and 3.0 mL of THF were combined in a vial and stirred
at room temperature overnight. Pentane was added to the mixture
creating a green precipitate. This green solid was filtered and rinsed
with pentane then dried in vacuo yiedling a dark-green solid (299.3 mg,
>99%). A crystal suitable for X-ray analysis was grown from slow
diffusion of pentane into a solution of (L2)FeBr2 in THF. Elemental
Analysis calculated: C, 51.31 H, 4.65 N, 7.18 found: C, 51.59 H, 4.88
N, 7.19.
ASSOCIATED CONTENT
■
S
* Supporting Information
(9) (a) Kim, J.; Shin-ya, S.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1997, 38, 3431−3434. (b) Alajarin, M.; Molina, P.;
Vidal, A. J. Nat. Prod. 1997, 60, 747−748.
(10) Toshiki, M.; Cheon, J.; Tsuchiya, G.; Araki, K. J. Chem. Soc.,
Perkin Trans. 2 2002, 862−865.
1
Experimental details, H and 13C NMR spectra, and crystal
structure data for (L2)FeBr2. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) Burchak, O. N.; Mugherli, L.; Ostuni, M.; Lacapere, J. J.;
Balakirev, M. Y. J. Am. Chem. Soc. 2011, 133, 10058−10061.
(12) Motoyama, T.; Sasabe, H.; Seino, Y.; Takamatsu, J.; Kido, J.
Chem. Lett. 2011, 40, 306−308.
AUTHOR INFORMATION
Corresponding Author
*louie@chem.utah.edu
Notes
■
(13) Horie, H.; Koyama, I.; Kurahashi, T.; Matsubara, S. Chem.
Commun. 2011, 47, 2658−2660.
The authors declare no competing financial interest.
(14) (a) Shen, Q.; Hartwig, J. F. Org. Lett. 2008, 10, 4109−4112.
(b) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423−
17429.
ACKNOWLEDGMENTS
■
The NIH (GM076125) and NSF (0911017) are acknowledged
for financial support. We thank Dr. J. Muller and Dr. Atta Arif
for providing HRMS and X-ray crystallographic data,
respectively.
(15) (a) Thomas, S.; Roberts, S.; Pasumansky, L.; Gamsey, S.;
Singaram, B. Org. Lett. 2003, 5, 3867−3870. (b) Londregan, A. T.;
Jennings, S.; Wei, L. Org. Lett. 2010, 12, 5254−5257.
(16) (a) Salem, M. A. I.; Madkour, H. M. F; Soliman, E. S. A.;
Mahmoud, N. F. H. Heterocycles 2000, 53, 1129. (b) Teague, S. J. J.
Org. Chem. 2008, 73, 9765−9766.
REFERENCES
■
(17) Cobalt: (a) Heller, B.; Reihsig, J.; Schulz, W.; Oehme, G. Appl.
Organomet. Chem. 1993, 7, 641−646. (b) Fatland, A. W.; Eaton, B. E.
(1) For selected reviews on [2 + 2 + 2] cycloadditions, see:
(a) Varella, J. A.; Saa,
́
C. Chem. Rev. 2003, 103, 3787−3801. (b) Kotha,
Org. Lett. 2000, 2, 3131−3133. (c) Bonaga, L. V. R.; Zhang, H.-C.;
S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741−4767.
(c) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307−2327.
(d) Heller, B.; Hapke, M. Chem. Soc. Rev. 2007, 36, 1085−1094.
(e) Shibata, T.; Tsuchikama, K. Org. Biomol. Chem. 2008, 6, 1317−
̃
Maryanoff, B. E. Chem. Commun. 2004, 2394−2395. (d) Hapke, M.;
Kral, K.; Fischer, C.; Spannenberg, A.; Gutnov, A.; Redkin, D.; Heller,
B. J. Org. Chem. 2010, 75, 3993−4003. (e) Garcia, P.; Evanno, Y.;
Gorge, P.; Sevrin, M.; Ricci, G.; Malacria, M.; Aubert, C.; Gandon, V.
́
1323. (f) Varela, J. A.; Saa, C. Synlett 2008, 17, 2571−2578. (g) Galan,
7562
dx.doi.org/10.1021/jo3012418 | J. Org. Chem. 2012, 77, 7555−7563

The Journal of Organic Chemistry
Article
Org. Lett. 2011, 13, 2030−2033. (f) Garcia, P.; Evanno, Y.; Gorge, P.;
Sevrin, M.; Ricci, G.; Malacria, M.; Aubert, C.; Gandon, V. Chem.
(37) Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.; Buchwald, S.
L. J. Org. Chem. 2008, 73, 284.
Eur. J. 2012, 18, 4337−4344. Nickel: (g) Bonnemann, H. Angew.
̈
Chem., Int. Ed. Engl. 1985, 24, 248−262. Rhodium: (h) Tanaka, K.;
Suzuki, N.; Nishida, G. Eur. J. Org. Chem. 2006, 3917−3922.
Titanium: (i) Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki, D.; Takayama,
Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7774−7780.
Photocatalytically: (j) Heller, B.; Sundermann, B.; Buschmann, H.;
Drexler, H.; You, J.; Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem.
2002, 67, 4414−4412.
(18) Additional PDAI class ligands were screened and are included in
the Supporting Information.
(19) Studies involving iron bis(imino)pyridine and bis(aldimino)
pyridine complexes: (a) Bart, S. C.; Chłopek, K.; Bill, E.; Bouwkamp,
M. W.; Lobkovsky, E.; Neese, F.; Weighardt, K.; Chirik, P. J. J. Am.
Chem. Soc. 2006, 128, 13901−13912. (b) Russell, S. K.; Milsmann, C.;
Lobkovsky, E.; Weyhermuller, T.; Chirik, P. J. Inorg. Chem. 2011, 50,
̈
3159−3169.
(20) See Supporting Information for details of control experiments.
(21) (a) Yamamoto, Y.; Kinpara, K.; Nishiyama, H.; Itoh, K. Adv.
Synth. Catal. 2005, 347, 1913−1916. (b) Yamamoto, Y.; Kinpara, K.;
Ogawa, R.; Nishiyama, H.; Itoh, K. Chem.Eur. J. 2006, 12, 5618−
5631.
(22) Cobalt: (a) Heller, B.; Sundermann, B.; Buschmann, H.;
Drexler, H.-H.; You, J.; Holzgrabe, U.; Heller, E.; Oehme, G. J. Org.
Chem. 2002, 67, 4414−4422. (b) Heller, B.; Reihsig, J.; Schulz, W.;
Oehme, G. Appl. Organomet. Chem. 1993, 7, 641−646. (c) Pietro, D.;
Ingrosso, G.; Lucherini, A.; Vanacore, D. J. Mol. Catal. 1987, 41, 261−
270. Rhodium: (d) Cioni, P; Civersi, P.; Ingrosso, G.; Lucherini, A.;
Ronca, P. J. Mol. Catal. 1987, 40, 337−357.
(23) Liu, Y.; Yan, X.; Yang, N.; Xi, C. Catal. Commun. 2011, 12,
489−492.
(24) Henke, B. R.; Drewry, D. H.; Jones, S. A.; Stewart, E. L.;
Weaver, S. L.; Wiethe, R. W. Bioorg. Med. Chem. Lett. 2001, 11, 1939−
1942.
(25) (a) Yamazaki, H.; Wakatsuki, Y. Tetrahedron Lett. 1973, 14,
3383−3384. (b) Bonnemann, H. Angew. Chem., Int. Ed. Engl. 1985, 24,
̈
248−262. (c) Diercks, R.; Eaton, B. E.; Gurtzgen, S.; Jalisatgi, S.;
̈
Matsger, A. J.; Radde, R. H.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1998,
120, 8247−8248. (d) Dazinger, G.; Torres-Rodrigues, M.; Kirchner,
K.; Calhorda, M. J.; Costa, P. J. J. Organomet. Chem. 2006, 691, 4434−
4445. (e) Dahy, A. A.; Yamada, K.; Koga, N. Organometallics 2009, 28,
3636−3649. (f) Dahy, A. A.; Koga, N. J. Organomet. Chem. 2010, 695,
2240−2250.
(26) (a) Takahashi, T.; Tsai, F. Y.; Kotora, M. J. Am. Chem. Soc.
2000, 122, 4994−4995. (b) Takahashi, T.; Tsai, F. Y.; Li, Y.; Wang,
H.; Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem.
Soc. 2002, 124, 5059−5067. (c) Eisch, J. J.; Ma, X.; Han, K. I.; Gitua, J.
N.; Kruger, C. Eur. J. Inorg. Chem. 2001, 77−88.
(27) Nishida, M.; Shiga, H.; Mori, M. J. Org. Chem. 1998, 63, 8606−
8608.
(28) Atkinson, R. S.; Grimshire, M. J. J. Chem. Soc., Perkin Trans. 1
1986, 1215−1217.
(29) Hu, Y.; Sun, Y.; Hu, J.; Zhu, T.; Yu, T.; Zhao, Q. Chem. Asian J.
2011, 6, 797−800.
(30) Ishizaki, M.; Hoshino, O. Tetrahedron 2000, 56, 8813−8819.
(31) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006,
128, 4586−4587.
(32) Han, Y.; Harlan, J.; Stoessel, P.; Frost, B. J.; Norton, J. R.; Miller,
S.; Bridgewater, B.; Xu, Q. Inorg. Chem. 2001, 40, 2942−2952.
(33) Tekavec, T. N.; Louie, J. J. Org. Chem. 2008, 73, 2641−2648.
(34) Apte, S.; Radetich, B.; Shin, S.; RajanBabu, T. V. Org. Lett. 2004,
6, 4053−4056.
(35) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2003, 125, 11516−
11517.
(36) Britovsek, G. J. P.; Bruce, M.; Gibson, V. C.; Kimberley, B. S.;
Maddox, P. J.; Mastroianni, S.; McTavish, S. J.; Redshaw, C.; Solan, G.
A.; Stroemberg, S.; White, A. J. P.; Williams, D. J. J. Am. Chem. Soc.
1999, 121, 8728−8740.
7563
dx.doi.org/10.1021/jo3012418 | J. Org. Chem. 2012, 77, 7555−7563