One-pot synthesis of pyrroles using a titanium-catalyzed multicomponent coupling procedure

Article abstract of DOI:10.1016/j.tet.2016.01.002

A simple one-pot procedure for the production of 2-carboxylpyrroles with 4-alkyl, 5-alkyl, 4-aryl, 4-aryl-5-alkyl, or 3,4-diaryl substitution patterns is presented. The procedure involves the titanium-catalyzed multicomponent coupling of alkynes, primary amines and isonitriles to give 1,3-diimines in situ; the multicomponent product is then treated with the ethyl ester of glycine hydrochloride to give the NH-pyrrole. The reaction can be carried out with the neutralized glycine ester or with the hydrochloride salt using DBU as a base. Yields of pyrrole based on starting alkyne varied from 25 to 65% over the one pot procedure, and in most cases only one regioisomer of the product is observed. Further, it is proposed that the regioselectivities of the reactions are a result of rate-determining ring closure after relatively fast transimination with glycine ethyl ester.

Full text of DOI:10.1016/j.tet.2016.01.002

Accepted Manuscript
One-pot synthesis of pyrroles using a titanium-catalyzed multicomponent coupling
procedure
Cody Pasko, Amila A. Dissanayake, Brennan S. Billow, Aaron L. Odom
PII:
S0040-4020(16)30002-3
10.1016/j.tet.2016.01.002
TET 27409
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 November 2015
Revised Date: 29 December 2015
Accepted Date: 4 January 2016
Please cite this article as: Pasko C, Dissanayake AA, Billow BS, Odom AL, One-pot synthesis of
pyrroles using a titanium-catalyzed multicomponent coupling procedure, Tetrahedron (2016), doi:
10.1016/j.tet.2016.01.002.
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ACCEPTED MANUSCRIPT
Graphical Abstract
One-pot synthesis of pyrroles using a
titanium-catalyzed multicomponent coupling
procedure
Leave this area blank for abstract info.
Cody M. Pasko, Amila A. Dissanayake, Brennan S. Billow and Aaron L. Odom*
Michigan State University, Department of Chemistry, 578 S. Shaw Ln, East Lansing, MI 48824

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
One-pot synthesis of pyrroles using a titanium-catalyzed multicomponent coupling
procedure
Cody Pasko, Amila A. Dissanayake, Brennan S. Billow and Aaron L. Odom
Michigan State University, Department of Chemistry, 578 S. Shaw Ln, East Lansing, MI 48824
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple one-pot procedure for the production of 2-carboxylpyrroles with 4-alkyl, 5-alkyl, 4-
aryl, 4-aryl-5-alkyl, or 3,4-diaryl substitution patterns is presented. The procedure involves the
titanium-catalyzed multicomponent coupling of alkynes, primary amines and isonitriles to give
1,3-diimines in situ; the multicomponent product is then treated with the ethyl ester of glycine
hydrochloride to give the NH-pyrrole. The reaction can be carried out with the neutralized
glycine ester or with the hydrochloride salt using DBU as a base. Yields of pyrrole based on
starting alkyne varied from 25-65% over the one pot procedure, and in most cases only one
regioisomer of the product is observed. Further, it is proposed that the regioselectivities of the
reactions are a result of rate-determining ring closure after relatively fast transimination with
glycine ethyl ester.
Available online
Keywords:
pyrrole; catalysis; multicomponent reaction; titanium
2015 Elsevier Ltd. All rights reserved
.
———
e-mail: odom@chemistry.msu.edu

2
Tetrahedron
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1. Introduction
hydroamination of diynes to give iminoalkynes that cyclize to
substituted pyrroles. The second synthesis involved a 4-
component coupling of alkyne, amine, and two equivalents of
isonitrile to give unusual 2,3-diaminopyrroles catalyzed by a
bis(indole)titanium complex.4,5
Multicomponent Reactions (MCR) allow tremendous diversity
from simple starting materials in a minimum of steps. Ideally, the
reactants will be inexpensive, using abundant elements as well.
Recently, we have developed synthetic protocols for the
synthesis of many different heterocyclic systems. These
syntheses rely on Earth-abundant, and inexpensive titanium to
catalyze an MCR that provides useful tautomers of 1,3-diimines.
One-pot reaction of these MCR products with a cyclizing agent
provides pyrazoles, quinolines, pyrimidines, isoxazoles, or
pyridines.1,2
There are several MCR methods for the synthesis of pyrroles,
and the field has been recently reviewed.6 Notable among these
are the traditional and modified Hantzsch syntheses involving,
for example, phenacyl bromide, acetylacetone, and amines
catalyzed by cyclodextrin (Scheme 1 top), which provides 2-
phenyl-3-keto-4-methylpyrroles with various substituents on the
pyrrole nitrogen.7
In this report, we describe conditions for the production of 2-
carboxylpyrrole derivatives in a one-pot procedure based on
titanium-catalyzed MCR. The reactions are generally
regioselective, and in some cases different regioisomeric
products from the same reactants can be favored by choice of
catalyst conditions.
The Paal-Knorr synthesis of pyrroles involves 1,4-diones and
their reactions with amines (Scheme 1 middle) and is perhaps one
of the best-known pyrrole syntheses.8
Nitrogen heterocycles in general, and pyrroles in particular,
are important frameworks in biology. Pyrrole rings are found in
heme, chlorophyll and numerous natural products. Pyrroles are
found in common dyes like BODIPY and many pharmaceuticals
like atorvastatin (Lipitor) and sunitinib (Sutent).
Scheme 1. Some “name reaction” examples of pyrrole
syntheses. (top) Variant of the Hantzsch pyrrole synthesis.
(middle) The Paal-Knorr synthesis of pyrroles. (bottom) The
Mataka variant of the Fischer-Fink pyrrole synthesis using ethyl
glycinate hydrochloride and 1,3-diones.
Another pyrrole synthesis of particular interest for placing this
work in context is a variant of the Fischer-Fink reaction reported
by Mataka and coworkers (Scheme 1 bottom).9 The reaction
involves condensation of a 1,3-dione with ethyl glycinate in
refluxing DMF. In the original publication, four 1,3-diones were
used, which gave yields from 18-74%.
What the reactions in Scheme 1 have in common is a reliance
on 1,3- or 1,4-diones, a common trait of many pyrrole syntheses.
One limitation on the variety of pyrroles accessible is the ease of
synthesis of these diones. Here, we use titanium multicomponent
coupling chemistry to generate 1,3-diimines, and we have
developed one-pot conditions for their use in the Mataka variant
of the Fischer-Fink reaction above. The methodology provides a
host of pyrrole compounds from simple starting materials in a
one-pot, 4-component sequence.
Chart 1. Pyrroles in biology, natural products, dyes, and
pharmaceuticals.
As seen in the top two examples in Chart 1, pyrroles are
commonly employed as ligands for metals, enabling a large
variety of functions in biology. In fact, we also employ them as
the ligands for our titanium catalysis to be discussed here (vide
infra).3
The general reaction sequence is shown in Scheme 2. The
origins of the non-hydrogen atoms in the pyrrole ring, along with
the bond disconnects, are also shown in the same scheme. The
regioselectivity shown is for 2-carboxyl-4,5-disubstituted
pyrroles, which are obtained for alkynes not bearing two
aromatic substituents as will be discussed in detail below.
Considering the importance of pyrroles, it is unsurprising that
significant attention has been paid to their synthesis. Indeed, our
group has published two quite different pyrrole syntheses based
on titanium-catalysis previously. The first involved

3
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Scheme 2. General reaction sequence for the titanium-
catalyzed MCR reaction to generate pyrroles. The
regioselectivity shown is for R2 or R3 = H or alkyl (vide infra).
2. Results and Discussion
For this study, we used two different titanium catalysts. The
ancillary ligands for the catalysts are pyrrole-based and are
prepared in a single step. The first ligand type, H2dpma, is
prepared by 5-component coupling (a double Mannich reaction)
between methylamine hydrochloride, 2 equiv. of formaline, and 2
equiv. of pyrrole. The second ligand type, H2dpm, is prepared by
condensation of pyrrole and acetone with catalytic trifluoroacetic
acid. Both ligands are readily accessed on large scales and react
with commercially available Ti(NMe2)4 to give catalysts A and B
in near quantitative yields.10,11
Scheme 3. Proposed mechanism for alkyne iminoamination to
produce tautomers of 1,3-diimines.
In some cases, electronic effects in the alkyne substrates
control the regioselectivities in the titanium-catalyzed MCR. This
is the case for alkynes containing one sp2-carbon, phenyl or
vinyl, attached to the triple bond. For these substrates, there is a
strong electronic preference for the sp2-carbon substituent to be
placed on the carbon between the two imines as shown in Eq 1.
The proposed cause for this is stabilization of the partial anionic
charge on the carbon attached to titanium by R3 (I in Scheme 3)
when this group is, for example, phenyl. However, relative
trapping rates of the two isomers will also contribute to the
observed regioselectivity.1
Chart 2. Structure of the titanium precatalysts used in this
study.
The first advantage of using pyrrole-based ligands for this
chemistry is the easily accessible multidentate ligands through
simple condensation reactions described above. The second
advantage is that relatively electron-deficient metal centers are
obtained, which results in faster catalysis rates.12
If the alkyne is terminal with one alkyl group, such as 1-
hexyne, then the two catalysts in Chart 2 can be used to obtain
either isomer as the major product of the reaction. This an
apparent steric effect controlled by the two different catalyst
structures of A and B. The production of the major isomer can be
further optimized by amine choice. For example, reaction of
aniline, 1-hexyne, tert-butylisonitrile, and catalyst A results in a
keto-aldimine 3CC product as the major isomer, as shown in Eq
2. Whereas, reaction of cyclohexylamine, 1-hexyne, tert-butyl
isonitrile, and catalyst B results in a dialdimine 3CC product as
the major isomer, as shown in Eq 3.13
The proposed mechanism for the titanium-catalyzed
multicomponent coupling reaction is shown in Scheme 3. The
two dimethylamido groups in the precatalyst are there to act as
protolyzable leaving groups for a primary amine, a reaction that
results in the formation of an imido (Ti=NR). The imido
undergoes reversible [2 + 2]-cyclization with the alkyne to an
azatitanacyclobutene
(I).
The
Ti–C
bond
of
the
Initially, the cyclization of the iminoamination product with
ethyl glycinate hydrochloride was optimized using an isolated
model diimine, the product of 3-component coupling between
phenylacetylene, cyclohexylamine, and tert-butylisonitrile
catalyzed by A. It was discovered that use of DBU as a base was
more reliable than several other bases, but triethylamine was
acceptable for some substrates. Use of DMSO as the solvent also
was found to be superior under the conditions examined over
other solvents like DMF, toluene and EtOH. An excess of the
ethyl glycinate hydrochloride improved yields, and the amount of
base should be slightly lower than the equiv. of ethyl glycinate
hydrochloride added. Typical conditions for the small-scale
cyclization are shown in Eq 4.
azatitanacyclobutene can be trapped by 1,1-insertion of the
isonitrile to give metallacycle II. Protonolysis of the Ti–C and
Ti–N bonds in the 5-membered metallacycle, shown stepwise
through species III and IV, gives the product and regenerates the
active catalyst.1
Catalyst A is a milder catalyst often used for terminal alkynes.
Catalyst B is a more reactive species that is typically used for
internal alkynes and bulkier substrates. There are regioselectivity
differences in some cases with the two catalysts as well as will be
explained.

4
Tetrahedron
cyclohexylacetylene results in a decrease of 1,3-diimine product
ACCEPTED MANUSCRIPT
discrimination (i.e. ratio of 1i:1j is 3.4:1), but still favoring the 2-
carboxyl-5-alkylpyrrole. For all sets of conditions, the major
isomer was easily separated by column chromatography.
Using precatalyst
B with cyclohexylamine favors the
production of 2-carboxyl-4-alkylpyrroles when using alkyl-
substituted terminal alkynes. Production of cyclohexylacetylene-
derived 1j is favored 19:1, whereas production of 1-hexyne-
derived 1h is favored by 12:1 using similar conditions (Scheme
4).
Table 1. Pyrroles derived from one-pot multicomponent
couplings and cyclizations involving terminal alkynes.
Yield
Entry
R1
R2
Product
(%)a
Alternatively, one can basify the ethyl glycinate hydrochloride
1a
Cy
50b
with K2CO3 and use the ethyl glycinate with a catalytic amount
of ammonium chloride, which is advisable for large-scale
syntheses to avoid excessive use of DBU.
1b
1c
Cy
Cy
47b
Yields from the ethyl glycinate hydrochloride/DBU and ethyl
glycinate/catalytic acid procedures were comparable. For
example, the one-pot synthesis of 1a (Eq. 5, Table 1) ethyl
glycinate hydrochloride with DBU gave 50% isolated yield.
Using ethyl glycinate with catalytic ammonium chloride gave
48% isolated yield on the same scale (Eq. 6). Pyrrole 1a was
prepared on a ~2 g scale using the procedure in Eq. 6 as well.
44b
1d
1e
Cy
Cy
40b
27b
1f
Ph
Ph
41c
56d
1g
35e
The results with terminal alkynes from the one-pot procedure
with 1 mmol of alkyne are provided in Table 1. In all cases, the
products are ethyl 2-carboxylpyrroles with the alkyne substituent
in either the 4- or 5-position as determined by the titanium MCR.
In aromatic- and vinyl-substituted alkynes only one isomer of the
pyrrole generally was observed with a traces of the other isomer
visible by GCMS in a few cases.
1h
1i
Cy
Ph
47c
48e
Catalyst structure can be used to control regiochemistry of the
MCR product, ultimately affecting pyrrole selectivity. Alkynes 1-
hexyne and cyclohexylacetylene were subjected to 1,3-diimine
formation conditions followed by one-pot pyrrole formation to
form different regioisomers depending on initial catalyst choice.
For example, use of 1-hexyne, aniline, tert-butylisonitrile and
precatalyst A gives preferentially product 1g (i.e. ratio of 1g:1h is
1j
Cy
aReaction conditions: Ti catalyst (10 mol%), toluene (2 mL), amine (2 mmol),
alkyne (1 mmol), isonitrile (1.2 mmol), 100 °C, 24 h; glycine ethyl ester
hydrochloride (3 mmol), DBU (2.8 mmol), and DMSO (4 mL), 120 °C, 18 h.
bReaction carried out with cyclohexylamine and catalyst A. Reaction carried
c
out with aniline and catalyst A.. dReaction carried out with aniline and
6.4:1).
Switching
substrates
from
1-hexyne
to

5
e
catalyst A at 80 °C. Reaction carried out with cyclohexylamine and catalyst
B.
glycinate to the iminoamination product (Scheme 4). In entry
ACCEPTED MANUSCRIPT
1g and 1i in Table 1 and all the examples in Table 2, one can
anticipate two possible products from the reaction of ethyl
glycinate with the 1,3-diimine: one product due to addition of the
glycine nitrogen to the ketimine side and one product due to
addition of nitrogen to the aldimine side.
R1NH2
NR1
R2 NR1
NHtBu
+
Precat. A or B
toluene, 100 °C
24 h
R2
+
NHtBu
R2
+
tBuNC
Cl
H3N
CO2Et
We can explain the regiochemical results for glycine addition
to the MCR product using a simple model based on the
assumption that the regiochemistry is determined by an
irreversible C–C bond formation during the initial ring closure.
Fast equilibria prior to this irreversible step are assumed to have
little affect on the regiochemical outcome and exchange of
amines in the 1,3-diimine 3-component coupling products are
considered fast. As a result, the glycine can be considered to be
in fast equilibrium between the two possible positions of the 1,3-
diimine (Figure 1).
If R2 = alkyl, then the favored ring closure is due to
nucleophilic attack on the aldimine carbon (Figure 1, top), which
gives the major isomer as the 2-CO2Et-4,5-disubstituted pyrrole.
If R2 = aryl, one can postulate that the aromatic group encourages
nucleophilic attack on the ketimine carbon, which results in a 2-
CO2Et-3,4-disubstituted pyrrole product (Figure 1, bottom).
DBU, DMSO
120 °C, 18 h
H
N
H
N
R2
CO2Et
CO2Et
+
R2
R1 = Ph, R2 = nBu, Precat. A 6.4 : 1
(1g/1h)
R1 = Cy, R2 = nBu, Precat. B
(1g/1h)
(1i/1j)
(1i/1j)
1 : 12
R1 = Ph, R2 = Cy, Precat. A
3.4 : 1
R1 = Cy, R2 = Cy, Precat. B
1 : 19
Scheme 4. The nature of the primary amine and precatalyst
can be used to control the regioselectivity of the multicomponent
coupling reaction and the pyrrole obtained as shown above using
1-hexyne and cyclohexylacetylene.
Table 2. Pyrroles derived from one-pot multicomponent
couplings and cyclizations involving internal alkynes with
isolated yields.
Entry
R2
R3
Product
Yield(%)a
65b,c
Me
2a
2b
51b,c
2c
25b
2d
37b,c
Figure 1. Model for the regiochemistry from the pyrrole synthesis using
glycine and the iminoamination products.
2e
2f
Me
Et
61b,c
To investigate the plausibility of these assertions, two
1
reactions were followed by H NMR, GC/MS, and GC/FID. In
these reactions of the MCR product, glycine ethyl ester and
catalytic ammonium chloride were added (Method B). The MCR
products employed were 3a and 3b shown below as their diimine
tautomers, which can be used to prepare pyrroles 2a and 2b. The
reactions were done at a relatively low temperature, 55 °C, to
observe transimination with little to no pyrrole formation.
Interestingly, the only new free amine observed during the
reaction at low pyrrole formation (<30%) was aniline. This could
imply the substitution is only occurring at the ketimine site;
however, it should be noted that Stefano and coworkers have
Et
29b
aReaction conditions: Ti catalyst B (10 mol%), toluene (2 mL), aniline (2
mmol), alkyne (1 mmol), isonitrile (1.2) mmol, 100 °C, 48 h; glycine ethyl
ester hydrochloride (3 mmol), DBU (2.8 mmol), and DMSO (4 mL), 120 °C,
18 h. bRegioisomer isolated determined by HSQC. cRegioisomer isolated
determined by single crystal X-ray diffraction.
In the majority of the cases in Table 1, there are no possible
regiochemical issues associated with the addition of the ethyl

6
Tetrahedron
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found that aliphatic amines will preferentially displace aromatic
The isolated yields of the reactions are from 25-65% for this
amines from imines.14 As a result, any tert-butylamine liberated
by reaction with excess glycine may be reacting further to
displace aniline. Consequently, observation of no free tert-
butylamine in the reaction does not necessarily imply that no
exchange is occurring with the aldimine site. In fact, there are
new compounds observed in the GC/MS with the appropriate
mass to be these di-tert-butylimines.15
2-step, one-pot multicomponent coupling route. This chemistry
allows for very rapid access to a large number of different
pyrroles for study, and we believe the chemistry will afford
efficient production of more complex pyrrole derivatives.
4. Experimental Section
4.1. General Considerations
All manipulations of air-sensitive compounds were carried out
in an MBraun drybox under a purified nitrogen atmosphere. All
glassware was heated at 150 °C for 4 h and stored in a drybox
under nitrogen. Toluene was purified by first sparging with dry
nitrogen to remove oxygen and then run through activated
alumina to remove water. 1H and 13C NMR spectra were recorded
on a VXR-500 spectrometer in CDCl3. Regiochemistry of
compounds 2a-2f, 3b and 3c were determined by coupled-HSQC
(see the Supporting Information). Melting points were measured
on a Mel-Temp II apparatus (Laboratory Devices Inc, USA) with
a mercury thermometer in an open capillary tube. Single crystal
X-ray diffraction data was collected in the Center for
Crystallographic Research at MSU. Ligands H2dpma18 and
H2dpm19 were prepared by literature methods. Ti(NMe2)2(dpma)
(A)10 and Ti(NMe2)2(dpm) (B)11 were made following literature
procedures. Alkynes were purchased either from Sigma-Aldrich
or GFS chemicals then distilled from CaO under dry nitrogen or
prepared using Sonogashira coupling.20 Amines were purchased
from Sigma-Aldrich and were distilled from KOH under dry
nitrogen. Triethylamine (TEA), glycine ethyl ester hydrochloride,
and sarcosine ethyl ester hydrochloride were all purchased from
Sigma-Aldrich and used as received. tert-Butylisonitrile was
prepared from tert-butylamine, CHCl3, and aqueous base
according to the literature procedure and purified by distillation
under dry nitrogen.21 tert-Butyldimethylsilyl chloride and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) were purchased from
Oakwood Chemicals and used as received. Dimethylsulfoxide
(DMSO) was purchased from Fisher Scientific and used as
received. Hexanes and ethyl acetate were purchased from
Mallinckrodt Chemicals and used as received.
In the case of reaction of 3a with glycine, no pyrrole
formation is observed at 55 °C for 14 h; however, some pyrrole is
formed (11% yield) in the reaction 3b, under the same conditions
with faster ring closure to product in this case due to the phenyl-
group on the ketimine carbon. In other words, all the data
collected were consistent with the model in Figure 1 where the
transimination site has little effect on the isomer and the phenyl
group on the imine carbon in 3b speeds ring-closure. It is
proposed that the relative rate of ring closure on the ketimine and
aldimine sites is the major factor in determining
regioselectivity.16,17 This model also explains Mataka and
coworkers’ regioselectivity results with 1,3-diketones.9
3. Concluding Remarks
The ethyl ester of glycine adds smoothly to the products of
titanium-catalyzed iminoamination, 1,3-diimines, to give NH-
pyrroles. The control of regioselectivity in the iminoamination
reaction allows selective placement of aromatic and other sp2-
hybridized carbons in the 4-position of the pyrrole product, and
all alkynes bearing one of these groups shows this selectivity.
Further, if the alkyne bears one alkyl substituent, e.g., the butyl-
group of 1-hexyne, this group can be placed in either the 4- or 5-
position with good selectivity depending on catalyst and
conditions chosen.
From the standpoint of the alkyne starting material for the
two-step sequence, one can briefly describe the accessible pyrrole
products as shown in Figure 2, where R = alkyl and C(sp2) = aryl
or vinyl.
Ethyl glycinate was basified for Methods B and C below by
dissolving ethyl glycinate hydrochloride in water and adding 2
equiv of K2CO3. The solution was extracted with
dichloromethane in three portions. The combined organic layers
were dried and filtered; then, the volatiles were removed by
rotary evaporation to give the ethyl glycinate as a clear to pale
yellow oil.
4.2. General procedure for 1,3-diimine Synthesis
A pressure tube was charged with a magnetic stir bar and Ti
precatalyst A or B (10 mol%) in toluene (2 mL), amine (2 mmol),
alkyne (1 mmol), and t-butylisonitrile (1.2 mmol) were added.
The pressure tube was sealed, removed from the drybox, and
placed into an oil bath preheated to 100-120 °C for 24-48 h. The
reaction was removed from the bath, and volatiles were removed
in vacuo.
4.3. General procedures for 2-carboxylpyrroles
4.3.1. Method A
The pressure tube from 1,3-diimine formation was charged
with glycine ethyl ester hydrochloride (420 mg, 3 mmol), DBU
(420 ꢀL, 2.8 mmol), and DMSO (4 mL). The pressure tube was
resealed and heated for 18 h at 120 °C in an oil bath. The reaction
was removed from the bath and extracted with DCM (40 mL).
The organic layer was washed with 10 % NaHCO3 (30 mL) and
with brine (30 mL). The aqueous layers were combined and
Figure 2. From the standpoint of the starting alkyne, the pyrroles shown
can be accessed based on the alkynes substituents using the chemistry
described here. R = alkyl, C(sp2) = aryl or vinyl

7
washed with DCM (40 mL). The organic layers were combined,
dried with anhydrous Na2SO4, and filtered. Volatiles were
removed, and the crude was purified by flash column
chromatography on silica gel with hexanes:ethyl acetate (4:1) and
1% TEA to afford the desired product.
JH = 2.1 Hz, Ar-H), 6.89 (1H, d, JHH = 8.4 Hz, Ar-H), 4.36
ACCEPTED MANUSCRIPT
H
(2H, q, JHH = 7.2 Hz, CH2), 3.94 (3H, s, CH3), 3.90 (3H, s, CH3),
1.39 (3H, t, JHH = 7.2 Hz, CH3). 13C{1H
NMR (CDCl3) δ 161.1,
149.2 147.8, 127.7, 126.8, 123.6, 118.8, 117.6, 112.2, 111.6,
108.9, 60.5, 56.0, 59.9, 14.5. HRMS (ES) m/z calcd. for
C15H16NO4 274.1079, found 274.1089.
}
4.3.2. Method B
4.4.4. Synthesis of ethyl 4-(4-benzyloxy)phenyl-
pyrrole-2-carboxylate (1d)
The pressure tube from 1,3-diimine formation was charged
with glycine ethyl ester (309 mg, 3 mmol), NH4Cl (22 mg, 0.4
mmol), and DMSO (4 mL). The pressure tube was resealed and
heated for 18 h at 120 °C in an oil bath. The reaction was
removed from the bath, and extracted with DCM (40 mL). The
organic layer was washed with 10% NaHCO3 (30 mL) and with
brine (30 mL). The aqueous layers were combined and washed
with DCM (40 mL). The organic layers were combined, dried
with anhydrous Na2SO4, and filtered. Volatiles were removed,
and the crude was purified by flash column chromatography on
silica gel with hexanes:ethyl acetate (4:1) and 1% TEA to afford
desired product.
1,3-diimine synthesis followed general procedure using Ti
precatalyst A (32.4 mg, 10 mol%), cyclohexylamine (230 ꢀL, 2
mmol), 1-ethynyl-4-benzyloxybenzene (208 mg, 1 mmol) and
heating at 100 °C for 24 h. Method A: The pyrrole was afforded
(128 mg, 40%) as a red solid. M.p. 146-147 °C. Rf (25%
1
EtOAc/hexane) 0.15. H NMR (CDCl3) δ 9.22 (1H, br s, N-H
pyrrole), 7.29-7.44 (7H, m, Ar-H), 7.12-7.13 (2H, m, Ar-H and
C-H pyrrole), 6.92-6.98 (2H, m, Ar-H and C-H pyrrole), 5.06
(2H, s, CH2), 4.33 (2H, q, JHH = 7.1 Hz, CH2), 1.37 (3H, t, JHH
=
7.1 Hz, CH3). 13C{1H
}
NMR (CDCl3) δ 161.2, 157.5, 137.1,
128.5, 127.9, 127.6, 127.4, 126.5, 126.4, 123.5, 118.7, 115.2,
112.1, 70.1, 60.3, 14.4. Elemental analysis: found %C 74.64, %H
5.89, %N 4.42; calcd. %C 74.75, %H 5.96, %N 4.36.
4.3.3. Method C
All materials from method B were scaled to alkyne (20
mmol).
4.4.5. Synthesis of ethyl 4-(cyclohexen-1-yl)-
pyrrole-2-carboxylate (1e)
4.4. Preparative details
1,3-diimine synthesis followed general procedure using Ti
precatalyst A (32.4 mg, 10 mol%), cyclohexylamine (230 ꢀL, 2
mmol), 1-cyclohexenylacetylene (123 ꢀL, 1 mmol) and heating
at 100 °C for 24 h. Method A: The pyrrole was afforded (59 mg,
27%) as a brown solid. M.p. 56-59 °C. Rf (25% EtOAc/hexane)
0.21. 1H NMR (CDCl3) δ 9.28 (1H, br s, N-H pyrrole), 6.95 (1H,
d, JHH = 1.7 Hz, C-H pyrrole), 6.88 (1H, d, JHH = 1.7 Hz, C-H
pyrrole), 5.98-6.00 (1H, m, C-H alkene), 4.28 (2H, q, JHH = 7.2
Hz, CH2), 2.24-2.27 (2H, m, CH2), 2.10-2.14 (2H, m, CH2), 1.68-
1.73 (2H, m, CH2), 1.58-1.63 (2H, m, CH2), 1.31-1.39 (3H, t, JHH
4.4.1. Synthesis of ethyl 4-phenyl-pyrrole-2-
carboxylate (1a)
1,3-diimine synthesis followed general procedure using Ti
precatalyst A (32.4 mg, 10 mol%), cyclohexylamine (230 ꢀL, 2
mmol), phenylacetylene (110 ꢀL, 1 mmol) and heating at 100 °C
for 24 h. Method A: The pyrrole was afforded (108 mg, 50%) as
a light brown solid. Method B: The pyrrole was afforded (104
mg, 48%) as a light brown solid. Method C: The pyrrole was
afforded (1.8 g, 42%) as a light brown solid. M.p. 97-99 °C (lit.20
Mp: 98-99 °C). Rf (25% EtOAc/hexane) 0.18. 1H NMR (CDCl3):
δ 9.25 (1H, br s, N-H pyrrole), 7.44-7.46 (2H, m, Ar-H), 7.27-
7.30 (2H, m, Ar-H), 7.14-7.18 (3H, m, Ar-H and C-H pyrrole),
4.28 (2H, q, JHH = 7.2 Hz, CH2), 1.31 (3H, t, JHH = 7.2 Hz, CH3).
13C{1H} NMR (CDCl3): δ 161.2, 134.5, 128.7, 126.5, 125.3,
123.7, 119.4, 112.4, 60.5, 14.4. Elemental analysis: found %C
72.45, %H 6.46, %N 6.59; calcd.; %C 72.54, %H 6.09, %N 6.51.
= 7.2 Hz, CH3). 13C{1H
} NMR (CDCl3) δ 161.4, 129.9, 122.8,
120.6, 118.4, 110.9, 60.3, 27.0, 25.3, 22.7, 22.3, 14.4. Elemental
analysis: found %C 71.29, %H 7.64, %N 6.30; calcd. %C 71.29,
%H 7.81, %N 6.39.
4.4.6. Synthesis of ethyl 5-(3-
tertbutyldimethylsilyloxy)propyl-pyrrole-2-
carboxylate (1f)
4.4.2. Synthesis of ethyl 4-(p-tolyl)-pyrrole-2-
carboxylate (1b)
1,3-diimine synthesis followed general procedure using Ti
precatalyst A (32.4 mg, 10 mol%), cyclohexylamine (230 ꢀL, 2
mmol), 1-t-butyldimethylsilyloxy-pent-4-yne (236 ꢀL, 1 mmol)
and heating at 100 °C for 24 h. Method A: The pyrrole was
afforded (128 mg, 41%) as a light brown solid. M.p. 63-64 °C. Rf
1,3-diimine synthesis followed general procedure using Ti
precatalyst A (32.4 mg, 10 mol%) , cyclohexylamine (230 ꢀL, 2
mmol), 1-ethynyl-4-methylbenzene (127 ꢀL, 1 mmol) and
heating at 100 °C for 24 h. Method A: The pyrrole was afforded
(108 mg, 47%) as a light orange solid. M.p. 166-167 °C (lit.20
Mp: 165-166 °C). Rf (25% EtOAc/hexane) 0.19. 1H NMR
(CDCl3) δ 9.27 (1H, br s, N-H pyrrole), 7.43 (2H, d, JHH = 3.1
Hz, Ar-H), 7.18-7.22 (m, 4H, Ar-H and C-H pyrrole), 4.36 (2H,
q, JHH = 7.2 Hz, CH2), 1.40 (3H, t, JHH = 7.2 Hz, CH3); 13C {1H}
NMR (CDCl3) δ 161.2, 135.9, 131.7, 129.5, 126.8, 125.2, 123.6,
119.1, 112.3, 60.5, 21.1, 14.5; elemental analysis: found %C
73.42, %H 6.49, %N 6.19; calcd. %C 73.34, %H 6.59, %N 6.11.
1
(25% EtOAc/hexane) 0.51. H NMR (CDCl3): δ 9.31 (1H, br s,
N-H pyrrole), 6.81 (1H, d, JHH = 3.3 Hz, C-H pyrrole), 5.94 (1H,
d, JHH = 3.3 Hz, C-H pyrrole), 4.27 (2H, q, JHH = 7.2 Hz, CH2),
3.62 (2H, t, JHH = 5.9 Hz, CH2), 2.69 (2H, t, JHH = 7.3 Hz, CH2)
1.79-1.85 (2H, quin, JHH = 7.3 Hz, 6.7 Hz, CH2), 1.31-1.40 (3H, t,
JHH = 7.2 Hz, CH3), 0.89 (9H, s), δ 0.03 (6H, s, CH3-Si). 13C{1H
}
NMR (CDCl3): δ 161.2, 138.1, 121.3, 115.8, 108.0, 61.9, 59.9,
31.9, 25.9, 24.1, 18.3, 14.5, –5.3. Elemental analysis: found %C
61.82, %H 9.13, %N 4.78; calcd. %C 61.69, %H 9.38, %N 4.50.
4.4.3. Synthesis of ethyl 4-(3,4-dimethoxy)phenyl-
pyrrole-2-carboxylate (1c)
4.4.7. Synthesis of ethyl 5-butyl-pyrrole-2-
carboxylate (1g)
1,3-diimine synthesis followed general procedure using Ti
precatalyst A (32.4 mg, 10 mol%), cyclohexylamine (230 ꢀL, 2
mmol), 1-ethynyl-3,4-dimethoxybenzene (162 mg, 1 mmol) and
heating at 100 °C for 24 h. Method A: The pyrrole was afforded
(121 mg, 44%) as a light yellow solid. M.p. 141-142 °C (lit.22
Mp: 136.3-137.5 °C). Rf (25% EtOAc/hexane) 0.06. H NMR
(CDCl3) δ 9.18 (1H, br s, N-H pyrrole), 7.15-7.18 (2H, m, C-H
pyrrole), 7.08 (1H, dd, JHH = 8.4 Hz, 2.1 Hz, Ar-H), 7.04 (1H, d,
1,3-diimine synthesis followed general procedure using Ti
precatalyst A (32.4 mg, 10 mol%), aniline (180 ꢀL, 2 mmol), 1-
hexyne (115 ꢀL, 1 mmol) and heating at 100 °C for 24 h. Method
A: The pyrrole was formed after heating at 80 °C for 18 h and
afforded (109 mg, 56%) as a brown oil. Rf (25% EtOAc/hexane)
0.49. 1H NMR (CDCl3): δ 9.40 (1H, br s, N-H pyrrole), 6.80 (1H,
d, JHH = 2.6 Hz, C-H pyrrole), 5.94 (1H, d, JHH = 2.6 Hz, CH-
1

8
Tetrahedron
pyrrole), 4.28 (2H, q, JHH = 7.2 Hz, CH2), 2.61 (2H, t, JHH = 7.5
(1H, d, JHH = 2.6 Hz, C-H pyrrole), 4.39 (2H, q, JHH = 7.2 Hz,
ACCEPTED MANUSCRIPT
Hz, CH2), 1.57-1.63 (2H, quin, JHH = 7.5 Hz, 7.0 Hz, CH2), 1.31-
1.35 (5H, m, CH2 and CH3), 0.89 (3H, t, JHH = 7.5 Hz, CH3).
CH2), 2.49 (3H, s, CH3), 1.41 (3H, t, JHH = 7.2 Hz, CH3); 13C
{1H
}
NMR (CDCl3) δ 161.5, 135.8 130.4, 128.4, 127.6, 125.8,
13C{1H
}
NMR (CDCl3): δ 161.5, 139.0, 121.0, 115.8, 107.8,
123.7, 120.6, 115.3, 60.2, 14.4, 12.8; elemental analysis: found
%C 73.38, %H 6.52, %N 6.04; calcd. %C 73.34, %H 6.59, %N
6.11. This compound was also characterized by single crystal X-
ray diffraction.
60.0, 31.4, 27.5, 22.2, 14.5, 13.7. Elemental analysis: found %C
67.74, %H 8.70, %N 7.24; calcd. %C 67.66, %H 8.78, %N 7.17.
4.4.8. Synthesis of ethyl 4-butyl-pyrrole-2-
carboxylate (1h)
4.4.12. Synthesis of ethyl 3,4-diphenyl-pyrrole-2-
carboxylate (2b)
1,3-diimine synthesis followed general procedure using Ti
precatalyst B (30.8 mg, 10 mol%), cyclohexylamine (230 ꢀL, 2
mmol), 1-hexyne (115 ꢀL, 1 mmol) and heating at 100 °C for 24
h. Method A: The pyrrole was afforded (68 mg, 35%) as a brown
oil. Rf (25% EtOAc/hexane) 0.46. 1H NMR (CDCl3): δ 8.91 (1H,
br s, N-H pyrrole), 6.77 (1H, d, JHH = 1.9 Hz, C-H pyrrole), 6.74
(1H, d, JHH = 1.9 Hz, C-H pyrrole), 4.31 (2H, q, JHH = 7.1 Hz,
CH2), 2.46 (2H, t, JHH = 7.5 Hz, CH2), 1.52-1.58 (2H, m, CH2),
1.34-1.38 (5H, m, CH2 and CH3), 0.91 (3H, t, JHH = 7.3 Hz, CH3).
1,3-diimine synthesis followed general procedure using Ti
precatalyst B (30.8 mg, 10 mol%), aniline (180 ꢀL, 2 mmol),
diphenylacetylene (178 mg, 1 mmol) and heating at 120 °C for
60 h. Method A: The pyrrole was afforded (148 mg, 51%) as a
pale yellow solid. M.p. 120-122 °C (lit.24 Mp: 118-119 °C). Rf
1
(25% EtOAc/hexane) 0.29. H NMR (CDCl3): δ 9.32 (1H, br s,
N-H pyrrole), 7.24-7.27 (5H, m, Ar-H), 7.14-7.18 (3H, m, Ar-H),
7.07-7.13 (3H, m, Ar- H and C-H pyrrole), 4.16 (2H, q, JHH = 7.2
13C {1H
}
NMR (CDCl3) δ 161.2, 134.5, 128.7, 126.5, 125.3,
Hz, CH2), 1.11-1.14 (3H, t, JHH = 7.2 Hz, CH3); 13C{1H
} NMR
123.7, 119.4, 112.4, 60.5, 14.4. Elemental analysis: found %C
67.07, %H 8.66, %N 7.25; calcd. %C 67.66, %H 8.76, %N 7.17.
HRMS (ES) m/z calcd. for C11H16NO2 194.1181, found
194.1185.
(CDCl3): δ 161.2, 134.5, 132.9, 130.8, 129.6, 129.3, 128.3, 128.2,
128.1, 127.4, 126.8, 120.2, 60.2, 14.0. Elemental analysis: found
%C 78.39, %H 5.81, %N 4.88; calcd. %C 78.33, %H 5.88, %N
4.81. This compound was also characterized by single crystal X-
ray diffraction.
4.4.9. Synthesis of ethyl 5-cyclohexyl-pyrrole-2-
carboxylate (1i)
4.4.13. Synthesis of ethyl 4-phenyl-5-(3-tert-
butyldimethylsilyloxy)propyl-pyrrole-2-carboxylate
(2c)
1,3-diimine synthesis followed general procedure using Ti
precatalyst B (30.8 mg, 10 mol%), aniline (180 ꢀL, 2 mmol), 1-
1,3-diimine synthesis followed general procedure using Ti
precatalyst A (32.4 mg, 10 mol%), aniline (180 ꢀL, 2 mmol),
cyclohexylacetylene (131 ꢀL, 1 mmol) and heating at 100 °C for
24 h. Method A: The pyrrole was afforded (104 mg, 47%) as a
light orange solid. M.p. 106-107 °C. Rf (25% EtOAc/hexane)
0.46. 1H NMR (CDCl3): δ 8.78 (1H, br s, N-H pyrrole), 6.82 (1H,
t, JHH = 2.9 Hz, C-H pyrrole), 5.97 (1H, t, JHH = 2.9 Hz, C-H
pyrrole), 4.29 (2H, q, JHH = 7.3 Hz, CH2), 2.57-261 (1H, m, C-H
cyclohexyl), 1.98-2.00 (2H, m, C-H cyclohexyl), 1.80-1.83 (2H,
m, C-H cyclohexyl), 1.71-1.74 (1H, m, C-H cyclohexyl), 1.21-
1.43 (8H, m, C-H cyclohexyl, CH3). 13C {1H} NMR (CDCl3) δ
161.4, 143.8, 120.9, 115.6, 106.1, 60.0, 36.9, 32.8, 26.1, 25.9,
14.6. HRMS (ES) m/z calcd. for C13H19NO2 221.1416, found
221.1417.
(tert-butyldimethylsilyloxy)-5-phenylpent-4-yne (274 mg,
1
mmol) and heating at 100 °C for 48 h. Method A: The pyrrole
was afforded (97 mg, 25%) as a red solid. M.p. 79-81 °C. Rf
1
(25% EtOAc/hexane) 0.40. H NMR (CDCl3): δ 9.35 (1H, br s,
N-H pyrrole), 7.36-7.40 (3H, m, Ar-H), 7.01-7.27 (2H, m, Ar-H),
7.01 (1H, d, JHH = 2.9 Hz, C-H pyrrole), 4.34 (2H, q, JHH = 7.1
Hz, CH2), 3.69 (2H, t, JHH = 6.1 Hz, CH2), 2.89-2.92 (2H, t, JHH
=
7.3 Hz, CH2), 1.87 (2H, pent, JHH = 7.3 Hz, CH2), 1.37 (3H, t, JHH
= 7.1 Hz, CH3), 0.91 (9H, s, CH3), 0.06 (6H, s, CH3-silyl).
13C{1H
} NMR (CDCl3): δ 161.1, 135.9, 134.1, 128.5, 127.9,
125.9, 123.7, 120.9, 115.3, 62.1 60.1, 31.7, 26.0, 22.9, 18.4, 14.6,
-5.3. Elemental analysis: found %C 67.97, %H 8.81, %N 3.62;
calcd. %C 68.17, %H 8.58, %N 3.61.
4.4.10. Synthesis of ethyl 4-cyclohexyl-pyrrole-2-
carboxylate (1j)
1,3-diimine synthesis followed general procedure using Ti
precatalyst B (30.8 mg, 10 mol%), cyclohexylamine (230 ꢀL, 2
mmol), cyclohexylacetylene (131 ꢀL, 1 mmol) and heating at 100
°C for 24 h. Method A: The pyrrole was afforded (106 mg, 48%)
as a bright orange solid. M.p. 68-69 °C. Rf (25% EtOAc/hexane)
0.37. 1H NMR (CDCl3): δ 8.86 (1H, br s, N-H pyrrole), 6.80 (1H,
t, JHH = 2.4 Hz, C-H pyrrole), 6.75 (1H, t, JHH = 2.4 Hz, C-H
pyrrole), 4.30 (2H, q, JHH = 7.2 Hz, CH2), 2.43-249 (1H, m, C-H
cyclohexyl), 1.93-1.95 (2H, m, C-H cyclohexyl), 1.77-1.82 (2H,
m, C-H cyclohexyl), 1.66-1.74 (1H, m, C-H cyclohexyl), 1.21-
1.43 (8H, m, C-H cyclohexyl, CH3). 13C {1H} NMR (CDCl3) δ
161.3, 133.0, 122.4, 119.0, 113.2, 60.2, 36.0, 34.5, 26.5, 26.2,
14.5. HRMS (ES) m/z calcd. for C13H19NO2 221.1416, found
221.1425.
4.4.14. Synthesis of ethyl 3,4-di(thiophen-2-yl)-
pyrrole-2-carboxylate (2d)
1,3-diimine synthesis followed general procedure using Ti
precatalyst B (30.8 mg, 10 mol%), aniline (180 ꢀL, 2 mmol), 1,2-
di(thiophene-2-yl)ethyne (190 mg, 1 mmol) and heating at 100
°C for 48 h. Method A: The pyrrole was afforded (112 mg, 37%)
as a yellow solid. M.p. 109-111 °C. Rf (25% EtOAc/hexane)
0.17. 1H NMR (CDCl3) δ 9.33 (1H, br s, N-H pyrrole), 7.38 (1H,
dd, JHH = 5.1 Hz, 1.1 Hz, C-H thiophene), 7.15 (1H, d, JHH = 3.3
Hz, C-H pyrrole), 7.11 (1H, dd, JHH = 5.1 Hz, 1.1 Hz, C-H
thiophene), 7.07 (1H, dd, JHH = 5.1 Hz, 3.3 Hz, C-H thiophene),
7.02 (1H, dd, JHH = 3.3 Hz, 1.1 Hz, C-H thiophene), 6.91 (1H, dd,
JHH = 5.1 Hz, 3.3 Hz, C-H thiophene), 6.78 (1H, dd, JHH = 3.3 Hz,
1.1 Hz, C-H thiophene), 4.22 (2H, q, JHH = 7.2 Hz, CH2), 1.19
4.4.11. Synthesis of ethyl 4-phenyl-5-methyl-
pyrrole-2-carboxylate (2a)
(3H, t, JHH = 7.2 Hz, CH3). 13C{1H
} NMR (CDCl3): δ 160.7,
136.0, 134.3, 128.6, 127.0, 126.6, 126.1, 124.2, 123.8, 121.7,
121.6, 120.8, 119.7, 60.5, 14.0. Elemental analysis: found %C
59.16, %H 4.68, %N 4.51; calcd. %C 59.38, %H 4.32, %N 4.62.
This compound was also characterized by single crystal X-ray
diffraction.
1,3-diimine synthesis followed general procedure using Ti
precatalyst B (30.8 mg, 10 mol%), aniline (180 ꢀL, 2 mmol), 1-
phenylpropyne (125 ꢀL, 1 mmol) and heating at 100 °C for 48 h.
Method A: The pyrrole was afforded (149 mg, 65%) as a pale
yellow solid. M.p. 124-126 °C (lit.23 Mp: 125.5 °C); Rf (25%
1
4.4.15. Synthesis of ethyl 4-(cyclohexen-1-yl)-5-
methyl-pyrrole-2-carboxylate (2e)
EtOAc/hexane) 0.31; H NMR (CDCl3) δ 9.63 (1H, br s, N-H
pyrrole), 7.41-7.46 (4H, m, Ar-H), 7.26-7.30 (1H, m, Ar-H), 7.07

9
1,3-diimine synthesis followed general procedure using Ti
ACCEPTED MANUSCRIPT
precatalyst B (30.8 mg, 10 mol%), aniline (180 ꢀL, 2 mmol), 1-
(cyclohex-1-enyl)propyne (135 ꢀL, 1 mmol) and heating at 100
°C for 48 h. Method A: The pyrrole was afforded (142 mg, 61%)
as a light brown solid. M.p. 99-100 °C. Rf (25% EtOAc/hexane)
0.31. 1H NMR (CDCl3) δ 8.94 (1H, br s, N-H pyrrole), 6.78 (1H,
d, JHH = 2.8 Hz, C-H pyrrole), 5.67-5.69 (1H, m, C-H alkene), δ
4.27 (2H, q, JHH = 7.2 Hz, CH2), 2.32 (3H, s, CH3), 2.24-2.27
(2H, m, CH2), 2.12-2.16 (2H, m, CH2), 1.69-1.73 (2H, m, CH2),
4. Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom, A. L. Org.
Lett. 2004, 6, 2957.
5. Barnea, E.; Majumder, S.; Staples, R. J.; Odom. A. L.
Organometallics 2009, 28, 3876.
6. Recent reviews on pyrrole synthesis: (a) Estévez, V.; Villacampa,
M.; Menéndez, J. C. Chem. Soc. Rev. 2010, 39, 4402. (b)
Schmuck, C.; Rupprecht, D. Synthesis 2007, 3095.
7. The original Hantzsch synthesis was a two-component reaction
between ethyl β-aminocrontonate and α-halocarbonyls. See
Roomi, M. W.; MacDonald, S. F. Can. J. Chem. 1970, 48, 1689.
8. Khaghaninejad, S.; Heravi, M. M. Adv. Heterocyclic Chem. 2014,
111, 95.
1.59-1.63 (2H, m, CH2), 1.32 (3H, t, JHH = 7.2 Hz, CH3). 13C{1H
}
NMR (CDCl3): δ 161.2, 134.5, 128.7, 126.5, 125.3, 123.7, 119.4,
112.4, 60.5, 14.4. Elemental analysis: found %C 72.13, %H 8.13,
%N 6.08; calcd. %C 72.07, %H 8.21, %N 6.00. This compound
was also characterized by single crystal X-ray diffraction.
9. Mataka, S.; Takahashi, K.; Tsuda, Y.; Tashiro, M. Synthesis 1982,
157.
10. Harris, S. A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2001,
40, 1987-1988.
4.4.16. Synthesis of ethyl 4,5-diethyl-pyrrole-2-
carboxylate (2f)
11. (a) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem.
Commun. 2003, 586. (b) Novak, A.; Blake, A. J.; Wilson, C.;
Love, J. B. Chem. Comm. 2002, 2796
12. (a) Swartz, D. L. II; Staples, R. J.; Odom, A. L. Dalton Trans.
2011, 40, 7762. (b) DiFranco, S. A.; Maciulis, N. A.; Staples, R.
J.; Batrice, R. J.; Odom, A. L. Inorg. Chem. 2012, 51, 1187. (c)
Bemowski, R. D.; Singh, A. K.; Bajorek, B. J.; DePorre, Y.;
Odom, A. L. Dalton Trans. 2014, 43, 12299.
1,3-diimine synthesis followed general procedure using Ti
precatalyst B (30.8 mg, 10 mol%), aniline (180 ꢀL, 2 mmol), 3-
hexyne (114 ꢀL, 1 mmol) and heating at 100 °C for 48 h. Method
A: The pyrrole was afforded (57 mg, 29%) as a brown solid. M.p.
53-54 °C (lit.25 Mp: 60-62 °C). Rf (25% EtOAc/hexane) 0.43. H
1
13. The regioselectivity in Eq. 2 is 3 : 1, and if B is used in place of A
the ratio is 1 : 1. The regioselectivity in Eq. 3 is 11 : 1, and if A is
used in place of B then the ratio is 9 : 1. Use of aniline as the
amine gives the major product in Eq. 2; whereas use of
cyclohexylamine gives the major product shown in Eq. 3.
Consequently, the amine and catalyst choice act together on
determining regioselectivity with alkyl-substituted alkynes.
14. Ciaccia, M.; Pilati, S.; Cacciapaglia, R.; Mandolin, L.; Di Stefano,
S. Org. Biomol. Chem. 2014, 12, 3282–3287.
15. Imine formation involving two different alkyl amines has been
found to favor the amine with higher hyperconjugation, e.g.,
isopropylamine displaces n-butylamine. Consequently, it is
possible that tert-butylamine will displace any of the other amine
sources in the reaction mixture, if 1,3-diimines behave similarly.
Ciaccia, M.; Caccipaglia, R.; Mencarelli, P.; Mandolini, L; Di
Stefano, S. Chem. Sci. 2013, 4, 2253–2261.
NMR (CDCl3): δ 8.99 (1H, br s, N-H pyrrole), 6.75 (1H, d, JHH
=
2.9 Hz, C-H pyrrole), 4.30 (2H, q, JHH = 7.2 Hz, CH2), 2.61 (2H,
q, JHH = 7.7 Hz, CH2), 2.40 (2H, q, JHH = 7.5 Hz, CH2), 1.35 (3H,
t, JHH = 7.2 Hz, CH3), 1.22 (3H, t, JHH = 7.7 Hz, CH3), 1.17 (3H, t,
JHH = 7.5 Hz, CH3). 13C{1H
} NMR (CDCl3): δ 161.3, 135.8,
123.6, 119.7, 115.1, 59.9, 19.2, 18.7, 15.4, 14.6, 13.8. Elemental
analysis: found %C 67.85, %H 8.75, %N 7.40; calcd. %C 67.66,
%H 8.78, %N 7.17.
Acknowledgments
The authors greatly appreciate the financial support of the
National Science Foundation (CHE-1265738). The authors
would also like to thank Dan Holmes for his help with the NMR
experiments.
16. Ring closure of the hemiaminal has been proposed as the rate
determining step in the Paal-Knorr synthesis. Mothana, B.; Boyd,
R. J. THEOCHEM 2007, 811, 97.
17. For discussions of Curtin-Hammett kinetics see (a) Seeman, J. I.
Chem. Rev. 1983, 83, 83–134. (b) Follett, A. D.; McNeill, K. J.
Am. Chem. Soc. 2005, 127, 844–845.
18. Li, A.; Turnas, A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem.
2002, 41, 6298-6306.
19. Littler, B. J.; Miller, M. A.; Hung, C-H.; Wagner, R. W.; O’Shea,
D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64,
1391−1396.
20. (a) Mujkic, M.; Lentz, D. Dalton Trans. 2012, 41, 839-849. (b)
Ban, H. S.; Minegishi, H.; Shimizu, K.; Maruyama, M.; Yasui, Y.;
Nakamura, H. Chem. Med. Chem. 2010, 5, 1236-1241. (c)
Marshall, J, A.; Dehoff, B. S. J. Org. Chem. 1986, 51, 863. (d)
Mio, M. J.; Kopel, L. C.; Braun, J. B.; Gadzikwa, T. L.; Hull, K.
L.; Brisbois, R. G.; Markworth, C. J.; Grieco, P. A. Org. Lett.
2002, 4, 3199-3202. (e) Aksin-Artok, Ö, Krause, N. Adv. Synth.
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Supplementary Material
1H and 13C NMR spectra for the purified pyrroles. HMQC
coupling constants for the pyrrole C–Hs and a brief discussion of
determination of regioselectivity. Some additional discussion of
transamination studies and some NMR and GC data from the
experiments. X-ray diffraction data for 2a, 2b, 2d, 2e and 3b
have been deposited with CCSD (1405632, 1405633, 1405634,
1417570, and 1417571).
References and notes
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