Synthesis of protected (1-phenyl-1 H -pyrrol-2-yl)-alkane-1-amines from phenylnitroso diels-alder adducts with 1,2-dihydropyridines

Article abstract of DOI:10.1021/jo4009996

The reductive cleavage of nitrosobenzene-derived cycloadducts with appropriately protected 1,2-dihydropyridines allows a novel and simple obtainment of substituted N-[1-(1-phenyl-1H-pyrrol-2-yl)alkylamides. This synthesis can also be carried out in a very simple, mild, and practical one-pot procedure without isolation of the corresponding nitrosobenzene cycloadduct by means of catalytic amounts of CuCl.

Full text of DOI:10.1021/jo4009996

Subscriber access provided by UNIV LAVAL
Note
Synthesis of Protected (1-Phenyl-1H-pyrrol-2-yl)-alkane-1-amines
from Phenylnitroso Diels-Alder Adducts with 1,2-Dihydropyridines
Francesco Berti, Valeria Di Bussolo, and Mauro Pineschi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4009996 • Publication Date (Web): 13 Jun 2013
Downloaded from http://pubs.acs.org on June 14, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of Protected (1ꢀPhenylꢀ1Hꢀpyrrolꢀ2ꢀyl)ꢀ
alkaneꢀ1ꢀamines from Phenylnitroso DielsꢀAlder
Adducts with 1,2ꢀDihydropyridines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Francesco Berti, Valeria Di Bussolo, and Mauro Pineschi*.
Dipartimento di Farmacia, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via
Bonanno 33, 56126 Pisa, Italy. pineschi@farm.unipi.it
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
1) Ph-N=O
R
9 examples
25-72%
N
R
N
2)
CuCl (cat), MeOH
NHPG
PG
Ph
also possible in a one-pot fashion
protected (α-branched)
2-pyrrolylamines
PG = Ac, Bz, Ts, Cbz
R = H, alkyl, phenyl
The reductive cleavage of nitrosobenzeneꢀderived cycloadducts with appropriately protected 1,2ꢀ
dihydropyridines allows a novel and simple obtainment of substituted Nꢀ[1ꢀ(1ꢀphenylꢀ1Hꢀpyrrolꢀ
2ꢀyl)alkylamides. This synthesis can also be carried out in a very simple, mild and practical oneꢀ
pot procedure without isolation of the corresponding nitrosobenzene cycloadduct by means of
catalytic amounts of CuCl.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 23
1
2
3
4
5
6
7
8
9
The preparation of pyrrole derivatives is of special importance as this nucleus is an integral
part of biologically important compounds.1 The synthesis of pyrroles can be accomplished in
several ways,2 but few of them are applicable to substituted Nꢀaryl pyrroles.3 Interestingly,
dihydroꢀ1,2ꢀoxazines 3, easily obtained by nitrosoꢀDielsꢀAlder cycloaddition of dienes 1 to
nitroso dienophiles 2, can be converted into 1ꢀphenyl pyrroles by photolysis,4 baseꢀmediated
rearrangement,5 under high temperature and pressure with palladium,6 or ruthenium catalysts,7
(Scheme 1). The use of Lewis acids such as BF3ꢀEt2O has been reported to give low yields of
pyrrole products, due the tendency of these compounds to undergo polymerization under these
reaction conditions.8 More recently, the reductive cleavage (NaBH4, Mo(CO)6 in CH3CNꢀH2O at
90 °C) of the NꢀO bond of dihydroꢀ1,2ꢀoxazines followed by an oxidation reaction with
manganese dioxide or DessꢀMartinꢀperiodinane of the resulting γꢀamino alcohol, afforded
substituted pyrroles.9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1
R1
R3
R4
R2
R1
R2
R3
R2
R3
O
N
refs 4-9
O
N
+
R5
R5
N
R5
R4
2
R4
1
3
R1
this work
R1
NHPG
Ph-N=O
PG
N
Ph
N
R1
N
O
N
PG
Ph
5
4
SCHEME 1. Obtainment of pyrroles from nitroso DielsꢀAlder cycloadducts.
It should be noted that all these reaction protocols that can be used to give pyrroles have
invariably been applied to monocyclic nitroso DielsꢀAlder cycloadducts (i.e. 1,2ꢀoxazines of type
3). To the best of our knowledge, the use of bicyclic nitroso DielsꢀAlder cycloadducts, such as 5,
as precursors for pyrroles has not been reported (Scheme 1). In principle, these compounds
2
ACS Paragon Plus Environment

Page 3 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
cannot afford a pyrrole derivative, unless a double ring fragmentation of the bicyclic nitroso
cycloadduct occurs.
7
8
9
We recently reported a novel preparation of Nꢀacetylꢀ1,2ꢀdihydropyridyl acetic acid methyl
ester 4a (see Scheme of Table 1) and its DielsꢀAlder reactions with nitroso dienophiles.10 The
reductive cleavage of the NꢀO bond showed some interesting features with inverse adducts
derived from acylnitroso dienophiles.10 Remarkably, the reductive cleavage of the NꢀO bond of
phenylnitroso direct cycloadduct 5a showed a completely different and, in some cases
unexpected behavior, which we now report in detail in Table 1. When direct adduct 5a was
treated with [Mo(CO)6] in a CH3CN/H2O mixture at 65 °C, only a retro DielsꢀAlder process was
found (entry 1, Table 1).10 Also the addition of NaBH4, commonly used in the reductive cleavage
of NꢀO bonds of oxazines,9,11 promoted the formation of the starting dihydropyridine 4a (entry
2). The use of an alane reagent such as AlH3, freshly prepared from LiAlH4 and sublimed
AlCl3,12 afforded a complex mixture of unidentified products (entry 3). Also SmI2 gave a
complex mixture in which the signals of starting material 5a were present (entry 4).13 To our
surprise, the use of titanocene(III) chloride (Cp2TiCl), generated in situ from Cp2TiCl2 and zinc
metal in the presence of alcoholic solvents afforded substantial amounts of pyrrole derivative 8a
without isolation of NꢀO cleaved product 6a (entries 5 and 6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 23
1
2
3
4
5
Table 1. Screening of reaction conditions for the reductive NꢀO cleavage of phenyl nitroso
cycloadduct 5a.a
6
7
COOMe
NHPh
reduction
conditions
+
8
9
+
COOMe
NHAc
Ac
N
Ph
N
N
RO
N
N
O
Ph
Ac COOMe
Ac
COOMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5a
4a
8a
6a, R= H
7a, R= Me
direct adduct
Entry
Reaction conditions
Products (%)b
(6a-7a / 4a / 8a)
<2 / >96 /<2
1
2
Mo(CO)6, CH3CN/H2O, 60 °C, 5h
Mo(CO)6, NaBH4, MeOH/H2O, 65 °C, 15h
AlH3, Et2O, 0 °C to rt, 5h
<2 / >96 /<2
3
complex mixture
complex mixture
<2 / 35 /65
4
SmI2, 0 °C to rt, 5h
5
Cp2TiCl, THF/MeOH, ꢀ30 °C to rt, 20h
Cp2TiCl, THF/EtOH, ꢀ30 °C to rt, 20h
TiCl3, MeOH/H2O, rt, 45 min
Zn, HCl, MeOH, rt, 15h
6
<2 / 42 /58
7
60 (7a), 40 (6a)
complex mixture
<15 / <2 / >80
<15 / <2 / >80 c
<10/ < 35 / >55
8
9
CuCl (1.0 eq), MeOH, rt, 3h
CuCl (0.2 eq), MeOH, rt, 18h
CuI (0.2 eq), MeOH, rt, 24h
10
11d
a
Unless stated otherwise, all reactions gave >95% conversion of 5a in the reported reaction
b
1
conditions. For details, see Supporting Information. Determined by H NMR of the crude
c
mixture. 72% Isolated yield of 8a after chromatographic purification. A complex mixture of
methoxylated products other than 7a was isolated as byꢀproduct. d Conversion 70%.
The obtainment of an Nꢀphenyl pyrrole derivative from an Nꢀphenyl nitroso cycloadduct of this
kind has not been previously reported, and can be admitted only by a tandem reductive cleavageꢀ
fragmentationꢀintramolecular amination. It should be noted that although the reaction started at ꢀ
30 °C, as previously reported for the NꢀO cleavage of Nꢀacylated bicyclic oxazines,14 it needed
several hours at room temperature to reach complete conversion of the Nꢀphenyl substrate. It was
also interesting to find that TiCl3, which is usually the preferred source of titanium(III), being
4
ACS Paragon Plus Environment

Page 5 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
commercially available as a solution in hydrochloric acid, did not afford pyrrole derivatives or
starting dihydropyridine 4a, but only promoted the reductive cleavage of the NꢀO bond
(compound 6a) accompanied by 1,2,3,6ꢀtetrahydropyridine 7a, which derives from the ring
opening with methanol, followed by reduction of the intermediate hydroxylamine (entry 7). It
was also found that a Ti(III) species is not essential to obtain pyrrole derivatives. For example,
simple zinc metal in hydrochloric MeOH at room temperature afforded compound 8a, albeit with
very low yield and in a complex reaction mixture (entry 8). The heterogeneous reaction
conditions and the long reaction time connected with the use of Cp2TiCl stimulated the search for
other procedures. A satisfactory solution was found by the use of stoichiometric amounts of CuCl
in MeOH at room temperature.15 To our delight, the reaction was complete in 3h at rt and pyrrole
8a was isolated with a good yield after chromatographic purification (entry 9). From the same
chromatography it was also possible to obtain in the second eluting fractions a mixture of
inseparable tetrahydropyridines, including compounds 6a and 7a. Two facts are worthy of
mention: i) the reaction can be carried out at room temperature and ii) also catalytic amounts of
CuCl (20 mol%) gave the same results, although it was necessary to use a prolonged reaction
time (entry 10). The use of catalytic amounts of CuI proved to be less effective and less selective
for the formation of the pyrrole derivative (entry 11). It should be noted that while the synthesis
of 2ꢀpyrrolylalanine has been reported in view of its peculiarity in peptide chemistry,16 the
synthesis of 2ꢀpyrrolylꢀβꢀalanine derivatives, such as 8a, has only few precedents which
furthermore have scarce preparative importance.17
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The scope of the synthesis of (1ꢀphenylꢀ1Hꢀpyrrolꢀ2ꢀyl)ꢀalkaneꢀ1ꢀamines from Nꢀ
phenylnitroso cycloadducts with a variety of 1,2ꢀdihydropyridines was examined in detail. In
general, the synthesis of 1,2ꢀdihydropyridines bearing different protecting groups (PG) on the
nitrogen and substituents at the 2ꢀposition 4b-l was accomplished by organometallic addition to
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 23
1
2
Nꢀprotected pyridinium salts (see Experimental Section).18 The subsequent use of nitrosobenzene
afforded with complete regioselectivity the corresponding 3ꢀoxaꢀ2,5ꢀdiazabicyclo[2.2.2]octꢀ7ꢀ
enes (5b-l), which were used as precursors of pyrrole derivatives 8b-l using catalytic amounts (20
mol%) of CuCl (procedure A, Table 2). With cycloadducts 5b and 5c derived from acetyl and
benzoyl protected dihydropyridines 4b and 4c, respectively, the corresponding pyrrole derivatives
were obtained with moderate yields after 16h at room temperature (entries 1 and 2, Table 2). On
the other hand, the use of sulfonyl or carbobenzyloxy protecting groups in the same reaction
conditions proved to be less effective (entries 3ꢀ7). In particular, Nꢀtosyl derived adduct 5d was
not reactive with CuCl at room temperature (entry 3). However, it was possible to obtain with a
good yield the corresponding pyrrole derivative just by warming the reaction mixture at 70 °C for
3 h (entry 4). On the other hand, Cbzꢀprotected adducts 5e and 5f mainly produced a complex
mixture of ring opening products even at room temperature (entries 5 and 6). The corresponding
pyrrole derivative 8f was obtained only with a low yield with the phenylꢀsubstituted compound
5f in refluxing methanol (entry 7) or in the simplified oneꢀpot procedure (vide infra, entry 15).
Moderate yields of pyrrole derivatives were obtained with nitrosobenzene cycloadducts with
substituted amide protected 1,2ꢀdihydropyridine (entries 8ꢀ10).
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As found for compound 5a,10 also direct adducts 5b-i showed some decomposition via retro
DielsꢀAlder reactions to the corresponding starting dihydropyridines 4b-i during
chromatographic purification on silica gel.12 To address this problem, a oneꢀpot twoꢀstep
procedure (procedure B) without the isolation of the intermediate nitrosobenzeneꢀ1,2ꢀ
dihydropyridine cycloadduct was in some cases applied (entries 11ꢀ15).
6
ACS Paragon Plus Environment

Page 7 of 23
The Journal of Organic Chemistry
1
2
3
4
Table 2 Synthesis of Protected (1ꢀphenylꢀ1Hꢀpyrrolꢀ2ꢀyl)ꢀalkaneꢀ1ꢀamines.a
5
6
7
R
Ph-N=O
CuCl (20 mol%)
MeOH
R
PG
8
9
N
Ph
N
R
N
N
O
NHPG
PG
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5a-l
4a-l
8a-l
Entry
Reaction
conditions
R
PG
Ac
Yield (%)b
(Product)
50 (8b)
1
2
A
A
A
Ac
A
A
Ac
A
A
A
B
CH3
CH3
H
PhCO
Ts
60 (8c)
3
<10% conversion
71 (8d)
4
H
Ts
5
H
Cbz
Cbz
Cbz
PhCO
Ac
complex mixture
<10% conversion
28 (8f)
6
Ph
7
Ph
8
PhCC
C6H13
Ph
65 (8g)
9
46 (8h)
10
11
12
13
14
Ac
60 (8i)
CH2COOCH3
Ac
52 (8a)
B
Ph
C6H13
Ph
PhCO
Ac
59 (8l)
B
37 (8h)
B
Ac
45 (8i)
15
a
B
Ph
Cbz
25 (8f)
Reaction conditions A: anhydrous CuCl (0.03 mmol), MeOH (1.15 mL),
bicycle 5 (0.15 mmol), 16h at rt. Reaction conditions B: Compound 4 (0.20
mmol), nitrosobenzene (0.40 mmol), CH2Cl2 (0.4 mL), 1h rt. Then, MeOH (1.54
b
mL) and anhydrous CuCl (0.04 mmol), 18ꢀ24 h at rt. Isolated yield after
chromatographic purification. c Reaction carried out at 70 °C for 3h.
For example, dihydropyridine 4a was allowed to react with nitrosobenzene (2.0 equiv) in CH2Cl2
at rt for 1 h. After evaporation of the solvent, methanol was added followed by anhydrous CuCl
(20 mol%), continuing the stirring for 24 hours. With this simplified procedure the overall yields
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 23
1
2
3
4
5
6
7
8
9
can be increased, as it is no more necessary to isolate the corresponding nitrosobenzeneꢀ
dihydropyridine cycloadduct (entries 11ꢀ15). In fact, compounds of type 5 can be isolated from
silica gel pretreated with NEt3 with low to moderate yields (35ꢀ71%), and they are invariably
obtained in mixture with the corresponding starting dihydropyridines. Without a reasonable
explanation, the reaction conditions B allow in one case the obtainment of the corresponding
pyrrole in milder reaction conditions (cfr entry 7 and entry 15). On the other hand, with a
particular substitution pattern (i.e. dihydropyridine 4g, containing a triple bond), the oneꢀpot
procedure cannot be applied.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As regards the reaction mechanism, it is plausible that the reducing agent in a protic solvent
reduces the NꢀO bond and generates the corresponding 1,2,3,6ꢀtetrahydropyridine A (Scheme 2).
To explain the ring fragmentation of the sixꢀmembered piperidine nucleus, it is proposed that
cyclic Nꢀacetylated hemiaminal A, which reasonably exists in equilibrium with the
corresponding openꢀchain amidoaldehyde B, undergoes an intramolecular ring closure to give the
fiveꢀmembered hemiaminal C. The subsequent dehydration of the hydroxypyrroline C followed
by oxidation with Cu(II) furnishes the pyrrole nucleus while regenerating the copper(I) catalyst. It
is important to emphasize that the transformation into pyrrole derivatives occurs effectively only
when the protecting group of the endocyclic piperidine nitrogen is sufficiently electronꢀ
withdrawing (PG = Ac, PhCO, Ts) to shift the equilibrium from species A to openꢀchain species
B. In fact, the use of Cbz as protecting group proved to be less effective for the formation of the
corresponding pyrrole derivatives, and complex mixtures of methoxy tetrahydropyridines were
observed as the main products.
8
ACS Paragon Plus Environment

Page 9 of 23
The Journal of Organic Chemistry
1
2
3
Cu(II)
4
5
6
7
8
9
N
R2
N
Cu(II)
Cu(I)
Ph
O
Cu(II)
Ph
Cu(I)
Ph
N
R1
O
N
R2
N
O
O
N
R2
A
O
R1
O
O
R1
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2 Cu(I)
2 Cu(II)
Cu(II)
N
R2
NHCOR1
Ph
R2
H
(II)Cu
N
N
R2
N
O
NHCOR1
Ph
Ph
O
R1
8
C
B
SCHEME 2. Schematization of the plausible mechanism for the formation of protected αꢀ
branched 2ꢀpyrrolylamines catalyzed by CuCl.
In summary, we have developed a novel elaboration of nitrosobenzene cycloadducts with
1,2ꢀdihydropyridines to give Nꢀphenyl pyrroles bearing unconventional substituents at the Cꢀ2
position. The procedure described complements the other known methods to obtain substituted
pyrroles from cyclic oxazines. In particular, it is now possible to obtain 2ꢀpyrrolylꢀβꢀalanine
derivatives and protected αꢀbranched 2ꢀpyrrolylamines by means of a reliable, simple procedure.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 23
1
2
3
4
EXPERIMENTAL SECTION
5
6
7
8
General Remarks and Materials: All reactions were carried out under an argon atmosphere in
flameꢀdried, modified (Kjeldahl shape) Schlenk flasks fitted with a glass stopper or rubber septa
under a positive pressure of argon. All reagents were purchased from commercially available
sources. Anhydrous CH2Cl2 on molecular sieves and MeOH (HPLC grade) were used as the
reaction solvents without any further purification. THF was distilled on sodium/benzophenone
ketyl. Solvents for extraction and chromatography were distilled before use. Analytical TLC were
performed on silica gel sheets with detection by exposure to ultraviolet light (254 nm) and/or by
immersion in an acidic staining solution of pꢀanisaldehyde in EtOH. Silica gel 60 was used for
flash chromatography. 1H NMR spectra were recorded at 250 MHz. Chemical shifts are reported
in ppm downfield from tetramethylsilane with the solvent resonance as the internal standard
(deuterochloroform: δ 7.26, deuteroacetonitrile: δ 1.94). Signal patterns are indicated as follows:
br s, broad singlet; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Coupling constants (J)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
are given in hertz (Hz). C NMR spectra were recorded at 62.5 MHz, with complete proton
decoupling. Chemical shifts are reported in ppm downfield from tetramethylsilane with the
solvent resonance as the internal standard (deuterochloroform: δ 77.0, deuteroacetonitrile: δ
1.32). Melting points were determined on a Kofler apparatus and are uncorrected. HRESIMS
were acquired in positive ion mode on a QꢀTOF premier spectrometer equipped with a
nanoelectrospray ion source.
Compounds 4a,10 4d,19 4e,20 4f,20 4g,21 4i,22 4l,22 5a,10 5i,23 5e,24 were prepared in accordance
with the indicated literature procedures.
1-(2-Methylpyridin-1(2H)-yl)ethanone (4b). Following a modification of a previously described
procedure,25 a 100 mL Schlenk tube was charged, under argon protection, with pyridine (0.80
mL, 10 mmol), anhydrous THF (15 mL) and MeMgI (1.5 M in Et2O, 13.3 mL, 20 mmol). The
10
ACS Paragon Plus Environment

Page 11 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
reaction mixture was cooled to ꢀ78 °C and freshly distilled AcCl (0.71 mL, 10 mmol) was
dropwise added over 5 minutes. The reaction was allowed to reach 0 °C and vigorously stirred
for 4 hours. The reaction mixture was poured into iceꢀwater and extracted with Et2O (3x20 mL).
The combined organic layers were dried over MgSO4 and filtered. Subsequent flash
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
chromatography (hexanes/AcOEt= 7/3) afforded 4b (600 mg, 44%) as an oil. H NMR (250
MHz, CDCl3), major rotamer δ 6.39 (d, 1H, J= 7.5 Hz), 5.86 (dd, 1H, J= 5.2 and 9.5 Hz), 5.71ꢀ
5.60 (m, 1H), 5.41ꢀ5.21 (m, 1H), 5.20ꢀ5.11 (m, 1H), 2.15 (s, 3H), 1.09 (d, 3H, J=6.4 Hz); 13C
NMR (62.5 MHz, CDCl3), major rotamer δ 169.0, 126.0, 124.4, 121.6, 120.0, 106.8, 46.5, 18.4.
HRMS (ESI) m/z: [M+Na+] Calcd for C8H11NONa 160.0733; Found 160.0725.
(2-Methylpyridin-1(2H)-yl)(phenyl)methanone (4c). Following a modification of a previously
described procedure,25 a 100 mL Schlenk tube was charged, under argon protection, with
pyridine (0.80 mL, 10 mmol), anhydrous THF (15 mL) and MeMgI (1.5 M in Et2O, 13.3 mL, 20
mmol). The reaction mixture was cooled to ꢀ78 °C and freshly distilled BzCl (1.2 mL, 10 mmol)
was dropwise added over 5 minutes. The reaction was allowed to react at ꢀ78 °C for 3 hours and
carefully quenched with NH4Cl satd solution (5 mL). The resulting mixture was extracted with
Et2O (3x15 mL). The evaporation of the dried (MgSO4) organic layers afforded a crude product
which was purified by flash chromatography (hexanes/AcOEt= 9/1) to give a 81/19 mixture of
1,2ꢀ and 1,4ꢀdihydropyridines. Compound 4c was isolated by preparative TLC (hexanes/CH2Cl2=
1
2/8) as an oil (996 mg, 50%). H NMR (250 MHz, CDCl3), major rotamer δ 7.64ꢀ7.36 (m, 5H),
6.26 (d, 1H, J= 5.5 Hz), 5.94 (dd, 1H, J= 5.5 and 9.5 Hz), 5.78ꢀ5.64 (m, 1H), 5.31ꢀ5.11 (m, 2H),
13
1.24 (d, 3H, J= 6.3 Hz); C NMR (62.5 MHz, CDCl3), major rotamer δ 169.5, 134.8, 133.3,
130.5, 128.3, 126.2, 125.6, 120.5, 106.3, 47.6, 12.1. HRMS (ESI) m/z: [M+Na+] Calcd for
C13H13NONa 222.0889; Found 222.0885.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 23
1
2
3
4
5
6
7
8
9
1-(2-Hexylpyridin-1(2H)-yl)ethanone (4h): Following a modification of a previously described
procedure,26 a 25 mL Schlenk tube was charged, under argon protection, with pyridine (0.40 mL,
5 mmol) and anhydrous THF (5 mL). The reaction mixture was cooled at ꢀ65 °C and
hexyllithium was added (2.3 M in hexanes, 2.13 mL, 5 mmol), followed by freshly distilled AcCl
(0.71 mL, 10 mmol). After 2 hours the reaction mixture was quenched with water (7.5 mL) and
NaHCO3 satd solution (1.5 mL), and extracted with CH2Cl2 (3x10 mL). The combined organic
phase was washed with brine, dried over MgSO4, filtered and concentrated to give an orange oil
that contained a mixture of 1,2ꢀ and 1,4ꢀdihydropyridine (55/45). Purification by flash
chromatography (hexanes/AcOEt= 7/3) afforded the title compound (446 mg, 43%) as a colorless
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
oil. H NMR (250 MHz, CDCl3), major rotamer δ 6.43 (d, 1H, J= 7.6 Hz), 5.91 (dd, 1H, J= 5.3
and 9.6 Hz), 5.68 (ddd, 1H, J= 1.1, 5.7 and 9.5 Hz), 5.37ꢀ5.26 (m, 1H), 5.17ꢀ5.05 (m, 1H), 2.16
13
(s, 3H), 1.82ꢀ1.17 (m, 10H), 0.95ꢀ0.80 (m, 3H); C NMR (62.5 MHz, CDCl3), major rotamer δ
169.2, 125.0, 123.0, 120.6, 107.5, 50.1, 34.4, 33.4, 29.3, 24.4, 22.5, 21.5, 21.2, 14.0. HRMS
(ESI) m/z: [M+Na+] Calcd for C13H21NONa 230.1521 found 230.1525
General procedure for the synthesis of 3-phenyl-2-oxa-3,6-diazabicyclo[2.2.2]oct-7-enes (5):
Two equivalents of nitrosobenzene were added at room temperature to a 0.5 M solution of 1,2ꢀ
dihydropyridine in CH2Cl2. The reaction mixture was stirred at rt and monitored by TLC
analysis. Removal of the solvent in vacuum below 30°C gave a residue that was then purified as
specified.
1-((1S*,4R*,6R*)-6-Methyl-2-phenyl-3-oxa-2,5-diazabicyclo[2.2.2]oct-7-en-5-yl)ethanone (5b):
Nitrosobenzene (215 mg, 2.0 mmol) was added to a solution of 4b (137 mg, 1.0 mmol) in 2 mL
of CH2Cl2 at room temperature. The reaction was allowed to stir for 90 min and concentrated at
rt to afford a dark brown semisolid. Silica gel column purification (hexanes/AcOEt= 7/3 + 5% of
1
Et3N) afforded 5b (131 mg, 54%) as a sticky oil containing 14% of 4b. H NMR (250 MHz,
12
ACS Paragon Plus Environment

Page 13 of 23
The Journal of Organic Chemistry
1
2
3
4
CDCl3), major rotamer δ 7.29ꢀ7.17 (m, 2H), 7.06ꢀ6.93 (m, 3H), 6.69ꢀ6.57 (m, 1H), 6.18ꢀ6.07 (m,
5
6
13
1H), 5.76 (dd, 1H, J= 1.0 and 5.5 Hz), 4.48ꢀ4.31 (m, 2H), 2.17 (s, 3H), 1.15ꢀ1.26 (m, 3H); C
7
8
9
NMR (62.5 MHz, CDCl3), major rotamer δ 169.7, 150.0, 129.0, 128.7, 127.3, 123.0, 117.4, 77.3,
62.3, 51.8, 21.8, 16.5. HRMS (ESI) m/z: [M+Na+] Calcd for C14H16N2O2Na 267.1104; Found
267.1109.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
((1S*,4R*,6R*)-6-Methyl-2-phenyl-3-oxa-2,5-diazabicyclo[2.2.2]oct-7-en-5-
yl)(phenyl)methanone (5c): A solution of 4c (200 mg, 1.0 mmol) and nitrosobenzene (215 mg,
2.0 mmol) in CH2Cl2 (2 mL) was stirred 2 h at room temperature. Flash chromatography
(hexanes/AcOEt=8/2 + 5% of Et3N) afforded a yellow semisolid (138 mg, 45%) containing ca.
1
10% of 4c. H NMR (250 MHz, CDCl3) δ 7.57ꢀ7.37 (m, 5H), 7.06ꢀ6.91 (m, 2H), 6.74ꢀ6.61 (m,
3H), 6.73ꢀ6.61 (m, 1H), 6.23ꢀ6.13 (m, 1H), 5.75 (d, 1H, J= 5.0 Hz), 4.74ꢀ4.60 (m, 1H), 4.49 (bt,
13
1H, J= 2.7 Hz), 1.39ꢀ1.27 (m, 3H); C NMR (62.5 MHz, CDCl3) δ 170.5, 150.0, 135.3, 130.4,
128.9, 128.6, 128.5, 128.3, 127.7, 127.5, 122.9, 117.3, 78.4, 62.1, 51.3, 16.4. HRMS (ESI) m/z:
[M+Na+] Calcd for C19H18N2O2Na 329.1260; Found 329.1255.
(1S*,4R*)-2-Phenyl-5-tosyl-3-oxa-2,5-diazabicyclo[2.2.2]oct-7-ene (5d): A solution of 4d (141
mg, 0.6 mmol) and nitrosobenzene (129 mg, 1.2 mmol,) in 1.2 mL of CH2Cl2 was stirred at room
temperature for 1.5 h. Removal of solvent gave a crude solid that was triturated with hexane and
1
methanol to afford a yellow solid (107 mg, 52%). M.p.= 115ꢀ116 °C. H NMR (250 MHz,
CDCl3) δ 7.84 (d, 2H, J= 8.3 Hz), 7.30 (d, 2H, J=8.6 Hz), 7.22ꢀ7.14 (m, 2H), 6.99ꢀ6.90 (m,
1H),6.89ꢀ6.82 (m, 2H), 6.71 (ddd, 1H, J= 2.0, 5.5 and 7.7 Hz), 6.13ꢀ6.02 (m, 2H), 4.47ꢀ4.40 (m,
1H), 3.62 (dd, 1H, J= 2.9 and 9.8 Hz), 3.31 (dd, 1H, J= 2.3 and 9.8 Hz), 2.41 (s, 3H); 13C NMR
(62.5 MHz, CDCl3) δ 149.9, 143.7, 135.0, 130.9, 129.6, 128.5, 127.9, 126.2, 123.0, 117.3, 77.4,
56.2, 45.3, 21.6. HRMS (ESI) m/z: [M+Na+] Calcd for C18H18N2O3SNa 365.0930; Found
365.0928.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 23
1
2
3
4
5
6
7
8
9
(1S*,4R*,6R*)-Benzyl 2,6-diphenyl-3-oxa-2,5-diazabicyclo[2.2.2]oct-7-ene-5-carboxylate (5e).
A solution of 4e (291 mg, 1.0 mmol) and nitrosobenzene (214 mg, 2.0 mmol,) in 2.0 mL of
CH2Cl2 was stirred at room temperature for 1 h. Subsequent flash chromatography
(hexanes/AcOEt= 9/1 + 5% Et3N) afforded the title compound as a brownish oil (179 mg, 45%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
containing ca 12% of starting 4e. H NMR (250 MHz, CD3CN) δ 7.61ꢀ7.17 (m, 11H), 7.12 (d,
2H, J= 7.8 Hz), 7.03 (t, 1H, J=7.3 Hz), 6.90 (bs, 1H), 6.79 (bs, 1H), 6.41 (bs, 1H), 5.90ꢀ5.73 (m,
1H), 6.19ꢀ5.38 (m, 3H), 4.82 (t, 1H, 2.7 Hz); 13C NMR (62.5 MHz, CD3CN) δ 156.5, 151.5,
151.3, 131.4, 130.4, 129.7, 129.6, 129.2, 128.9, 128.7, 128.5, 127.9, 127.8, 127.4, 123.7, 76.8,
67.8, 62.9, 59.6. HRMS (ESI) m/z: [M+Na+] Calcd for C25H22N2O3Na 421.1523; Found
421.1520.
Phenyl((1S*,4R*,6R*)-2-Phenyl-6-(phenylethynyl)-3-oxa-2,5-diazabicyclo[2.2.2]oct-7-en-5-
yl)methanone (5g): A solution of 4g (114 mg, 0.4 mmol) and nitrosobenzene (86 mg, 0.8 mmol,)
in 0.8 mL of CH2Cl2 was stirred at room temperature for 1 hour. Removal of solvent provided a
sticky oil which was purified by flash chromatography (hexanes/AcOEt=9/1+ 5% Et3N). The title
compound was recovered (82 mg, 52%) as a semisolid. The sample was not analytically pure as
it contained ca 12% of starting 4g. 1H NMR (250 MHz, CDCl3) (major rotamer) δ 7.59ꢀ6.64 (m,
13
15H), 6.84 (bs, 1H), 6.38 (t, 1H, J= 7.0 Hz), 5.90 (bs, 1H), 5.52 (bs, 1H), 4.85 (bs, 1H); C
NMR (62.5 MHz, CDCl3) δ 169.9, 149.4, 134.4, 131.8, 130.7, 129.8, 129.2, 128.7, 128.5, 128.3,
128.1, 127.7, 123.4, 122.2, 117.5, 84.8, 83.0, 78.0, 60.9, 47.0. HRMS (ESI) m/z: [M+Na+] Calcd
for C26H20N2ONa 415.1417; Found 415.1412.
1-((1S*,4R*,6R*)-6-Hexyl-2-phenyl-3-oxa-2,5-diazabicyclo[2.2.2]oct-7-en-5-yl)ethanone (4h):
A solution of 4h (207 mg, 1.0 mmol) and nitrosobenzene (215 mg, 2.0 mmol) in CH2Cl2 (2 mL)
was stirred 1 h at room temperature. Flash chromatography (hexanes/AcOEt= 8/2) afforded the
1
title compound (176 mg, 56%) as a brown oil. H NMR (250 MHz, CDCl3), major rotamer δ
14
ACS Paragon Plus Environment

Page 15 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
7.28ꢀ7.16 (m, 2H), 7.03ꢀ6.92 (m, 3H), 6.67ꢀ6.52 (m, 1H), 6.22ꢀ6.06 (m, 1H), 5.76 (d, 1H, J= 5.7
Hz), 4.60ꢀ4.46 (m, 1H), 4.37ꢀ4.24 (m, 1H), 2.16 (s, 3H), 1.47ꢀ1.17 (m, 10H), 0.97ꢀ0.79 (m, 3H).
13C NMR (62.5 MHz, CDCl3), major rotamer δ 170.0, 150.2, 129.2, 128.5, 127.0, 123.0, 117.5,
77.4, 60.2, 56.3, 31.5, 30.4, 29.1, 25.8, 22.4, 13.9. HRMS (ESI) m/z: [M+Na+] Calcd for
C19H26N2O2Na 337.1886; Found 337.1991.
((1S*,4R*,6R*)-2,6-Diphenyl-3-oxa-2,5-diazabicyclo[2.2.2]oct-7-en-5-yl)(phenyl)methanone (5l):
A solution of 4l (261 mg, 1.0 mmol) and nitrosobenzene (214 mg, 2.0 mmol) in 2.0 mL of
CH2Cl2 was stirred at room temperature 30 min. Removal of solvent provided a sticky oil
purified by flash chromatography (hexanes/AcOEt=8/2+ 5% Et3N). The title compound was
recovered after trituration (methanol) (224.7 mg, 61%) as a semisolid containing ca 13% of 4l.
1H NMR (250 MHz, CDCl3) δ 7.70ꢀ6.76 (m, 16H), 6.05 (d, 1H, J= 4.7 Hz), 5.98 (app t, 1H,
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
J=6.7 Hz), 5.69 (bs, 1H), 4.73 (bs, 1H). C NMR (62.5 MHz, CDCl3) δ 170.3, 149.8, 137.4,
134.9, 130.8, 128.7, 128.4, 128.3, 123.8, 127.8, 127.7, 126.5, 123.1, 121.1, 117.3, 79.1, 63.0,
57.7. HRMS (ESI) m/z: [M+Na+] Calcd for C24H20N2O2Na 391.1417 found 391.1412.
TiCl3-mediated reduction of compound 5a (Table 1, entry 7): A 25 mL roundꢀbottom flask
was charged in this order with sodium acetate (300 mg, 3.65 mmol), methanol (1.25 mL), water
(0.875 mL), and compound 5a (91 mg, 0.30 mmol). The reaction mixture was stirred at room
temperature while 1.2 mL of a 20% TiCl3 solution in water was dropwise added. After 45 min
the solution was poured in 6 mL of water and extracted with AcOEt (4x8 mL). Combined
organic fractions were washed twice with 5 mL of 5% Na2CO3 to remove trace of acetic acid,
and once with 5 mL of brine. Evaporation of the dried (MgSO4) organic phase afforded a sticky
oil that was subjected to flash chromatography (hexanes/AcOEt= 5/5 +5% Et3N, Rf=0.09) to give
methyl
2-((2S,3R)-1-acetyl-6-hydroxy-3-(phenylamino)-1,2,3,6-tetrahydropyridin-2-yl)acetate
1
(6a) as an oil (32 mg, 35%). H NMR (250 MHz, CDCl3) δ 7.26ꢀ7.16 (m, 2H), 6.82ꢀ6.63 (m,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 23
1
2
3
4
5
6
7
8
9
3H), 6.10ꢀ5.97 (m, 3H), 4.54 (t, 1H, J= 7.2 Hz), 4.03ꢀ3.94 (m, 1H), 3.70 (s, 3H), 2.90 (dd, 1H, J=
7.5 and 17.0 Hz), 2.69 (dd, 1H, J= 7.0 and 17.0 Hz), 1.69 (s, 3H). 13C NMR (62.5 MHz, CDCl3)
δ173.7, 171.6, 145.7, 129.7, 129.4, 125.4, 118.5, 113.3, 70.3, 51.9, 50.6, 49.8, 37.3, 21.4. HRMS
(ESI) m/z: [M+Na+] Calcd for C16H20N2O4Na 327.1315; Found 327.1312.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The faster eluting fraction of above flash chromatography (Rf=0.30) afforded Methyl 2-
((2S*,3R*,6S*)-1-acetyl-6-methoxy-3-(phenylamino)-1,2,3,6-tetrahydropyridin-2-yl)acetate (7a)
1
(48 mg, 50%) as yellow solid. M.p.=123ꢀ125 °C; H NMR (250 MHz, CDCl3) δ 7.25ꢀ7.16 (m,
2H), 6.81ꢀ6.70 (m, 1H), 6.66ꢀ6.37 (m, 2H), 6.05 (dd, 1H, J= 3.4 and 10.1 Hz), 6.01ꢀ5.91 (m,
2H), 4.60 (dd, 1H, J= 5.9 and 9.3 Hz), 3.90ꢀ3.81 (m, 1H), 3.72 (s, 3H), 3.64 (d, 1H, J= 5.1 Hz),
3.31 (s, 3H), 3.05 (dd, 1H, J= 9.5 and 17 Hz), 2.63 (dd, 1H, J= 5.8 and 17 Hz), 2.02 (s, 3H). 13C
NMR (62.5 MHz, CDCl3) δ 173.2, 171.7, 145.6, 129.8, 129.0, 125.1, 118.4, 112.8, 75.7, 56.4,
51.8, 50.8, 49.9, 36.7, 21.6. HRMS (ESI) m/z: [M+Na+] Calcd for C17H22N2O4Na 341.1472
found 341.1466.
General procedures for the synthesis of protected (1-phenyl-1H-pyrrol-2-yl)-alkane-1-
amines. Method A: Anhydrous CuCl (3.0 mg, 0.03 mmol) was charged into a dried Schlenk
tube followed by a methanol solution (0.13 M) of nitrosobenzene cycloadduct 5 (0.15 mmol).
The reaction mixture was stirred at room temperature and monitored by TLC analysis up to
complete consumption of the cycloadduct (ca 16h). After evaporation of the solvent, the crude
mixture was partitioned between CH2Cl2 and water and the aqueous layer extracted again with
CH2Cl2. The combined organic layers were dried over MgSO4 and filtered. The crude reaction
mixture was then purified by chromatography on silica gel as specified.
Method B (one-pot procedure): Nitrosoarene (2.0 equiv) was added to a solution of 1,2ꢀ
dihydropyridine 4 in CH2Cl2 (0.5 M) at room temperature and the reaction mixture was
vigorously stirred until the 1,2ꢀdihydropyridine was consumed (TLC analysis, usually 1h). The
16
ACS Paragon Plus Environment

Page 17 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
solvent was removed under a vacuum at room temperature and the residue was diluted with
MeOH under a flow of argon. A catalytic amount of anhydrous CuCl (20 mol %) was added and
the reaction was allowed to proceed at room temperature until the cycloadduct 5 was consumed
(16ꢀ24 hours). After evaporation of the solvent, the crude mixture was partitioned between
CH2Cl2 and water and the aqueous layer extracted again with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered and evaporated under a vacuum. The crude reaction
mixture was then purified by chromatography on silica gel.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 3-acetamido-3-(1-phenyl-1H-pyrrol-2-yl)propanoate (8a). (Table 1, entry 10): Following
general procedure A, a 10 mL dried Schlenk tube was charged with anhydrous CuCl (3.0 mg,
0.03 mmol), methanol (1.15 mL) and bicycle 5a (46 mg, 0.15 mmol). The reaction was
vigorously stirred at room temperature for 16 hours. After the usual workꢀup, the crude reaction
mixture was subjected to flash chromatography (hexanes/AcOEt= 2/3) to afford 8a (31 mg,
72%), as a pale brown amorphous solid; 1H NMR (250 MHz, CD3CN) δ 7.53ꢀ7.34 (m, 5H); 6.81
(dd, 1H, J = 1.8, 2.9 Hz); 6.60 (m, 1H, exchange with D2O, NH); 6.28 (ddd, 1H, J = 1.0, 1.8, 3.8
Hz); 6.20 (dd, 1H, J = 2.8, 3.8 Hz); 5.22 (apparent q, 1H, J = 7.5 Hz); 3.54 (s, 3H); 2.76 (d, 2H, J
= 7.5 Hz); 1.78 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 171.4, 168.4, 139.4, 131.7, 129.3, 127.8,
126.2, 123.4, 108.2, 107.2, 51.7, 42.5, 38.8, 23.0. HRMS (ESI) m/z: [M+Na+] Calcd for
C16H18N2O3Na 309.1210; Found 309.1213.
N-(1-(1-Phenyl-1H-pyrrol-2-yl)ethyl)acetamide (8b). (Table 2, entry 1): Following general
procedure A, a 10 mL dried Schlenk tube was charged with anhydrous CuCl (4.0 mg, 0.04
mmol), methanol (1.53 mL) and bicycle 5b (45 mg, 0.20 mmol). After 16 hours, the usual workꢀ
up afforded a crude mixture that was purified by preparative TLC (hexanes/AcOEt= 1/1) to
afford 11b as a colorless solid (23 mg, 50%); M.p.= 114ꢀ117 °C; 1H NMR (250 MHz, CDCl3) δ
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 23
1
2
3
4
5
6
7
8
9
7.49ꢀ7.24 (m, 5H), 6.80 (s, 1H), 6.31ꢀ6.20 (m, 2H), 5.41 (d, 1H, J= 6.25 Hz), 5.19ꢀ5.05 (m, 1H),
1.73 (s, 3H), 1.45 (d, 3H, J= 6.75 Hz); 13C NMR (62.5 MHz, CDCl3) δ 168.1, 139.6, 134.5,
129.3, 127.7, 126.0, 123.2, 108.0, 106.9, 41.6, 23.0, 20.9. HRMS (ESI) m/z: [M+Na+] Calcd for
C14H16N2ONa 251.1151; Found 251.1158.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(1-(1-Phenyl-1H-pyrrol-2-yl)ethyl)benzamide (8c). (Table 2, entry 2): Following general
procedure A, a 10 mL dried Schlenk tube was charged with anhydrous CuCl (0.03 mmol, 3.0
mg), methanol (1.15 mL) and bicycle 5c (46 mg, 0.15 mmol). The reaction was vigorously stirred
at room temperature for 16 hours. The usual work up gave a crude solid that was purified by
flash chromatography (hexanes/AcOEt= 4/1) to afford 8c (26.1 mg, 60%) as a white solid;
1
M.p.=106ꢀ109 °C; H NMR (250 MHz, CDCl3) δ 7.58ꢀ7.27 (m, 10H), 6.83 (dd, 1H, J= 1.8 and
2.7 Hz), 6.36 (ddd, 1H, J=0.5, 1.8 and 3.5 Hz), 6.30ꢀ6.25 (m, 1H), 6.05 (d, 1H, J= 7.6 Hz), 5.41ꢀ
5.27 (m, 1H), 1.57 (d, 3H, J= 6.7 Hz); 13C NMR (62.5 MHz, CDCl3) δ 165.8, 139.6, 134.4,
131.2, 129.3, 128.3, 127.7, 126.7, 125.9, 123.3, 108.0, 107.1, 42.0, 20.8. HRMS (ESI) m/z:
[M+Na+] Calcd for C19H18N2ONa 313.1311; Found 313.1314.
4-Methyl-N-((1-phenyl-1H-pyrrol-2-yl)methyl)benzenesulfonamide (8d). (Table 2, entry 4).
Following method A, a 10 mL dried Schlenk tube was charged with anhydrous CuCl (0.03
mmol, 3.0 mg), methanol and 5d (52 mg, 0.15 mmol). The reaction mixture was stirred at 70 °C
for 3 hours. The usual workꢀup afforded a crude reaction mixture that was purified by preparative
1
TLC to give the title compound (34 mg, 71%), as a pale yellow solid; M.p.=115ꢀ117 °C; H
NMR (250 MHz, CDCl3) δ 7.60 (app d, 2H, J= 8.3 Hz), 7.42ꢀ7.33 (m, 3H), 7.30ꢀ7.15 (m, 4H),
6.76 (dd, 1H, J= 2.7, 1.9 Hz), 6.20ꢀ6.10 (m, 2H), 4.34 (t, 1H, J= 5.5 Hz), 4.09 (d, 2H, J= 5.7 Hz),
2.43 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 143.3, 139.1, 136.5, 129.6, 129.3, 127.6, 127.1,
125.5, 123.5, 110.7, 108.5, 39.2, 21.5. HRMS (ESI) m/z: [M+Na+] Calcd for C18H18N2O2SNa
349.0981; found 349.0985.
18
ACS Paragon Plus Environment

Page 19 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Benzyl (phenyl(1-phenyl-1H-pyrrol-2-yl)methyl)carbamate (8f). (Table 2, entry 7): In accordance
with general procedure A, a 10 mL flameꢀdried Schlenk tube was charged with anhydrous CuCl
(3.0 mg, 0.03 mmol), methanol (1.15 mL) and cycloadduct 5f (60 mg, 0.15 mmol). The reaction
mixture was stirred at 70 °C for 2 hours. The usual workꢀup provided a complex reaction mixture
from which the title compound was isolated by preparative TLC (hexanes/AcOEt = 7 :3) (16 mg,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
28%) as a brownish oil. H NMR (250 MHz, CDCl3) δ 4.46ꢀ7.11 (m, 15H), 6.77 (dd, 1H J=1.9,
2.6 Hz), 6.20 (t, 1H, J=3.2 Hz), 6.04ꢀ5.98 (m, 1H), 5.92 (d, 1H, J=8.0 Hz), 5.27 (d, 1H, J=7.5
Hz), 5.08ꢀ4.91 (m, 2H); 13C NMR (62.5 MHz, CDCl3) δ 154.9, 141.0, 139.5, 136.4, 133.5,
129.1, 128.5, 128.4, 128.1, 127.7, 127.4, 127.0, 126.5, 123.3, 108.7, 108.1, 66.8, 52.0. HRMS
(ESI) m/z: [M+Na+] Calcd for C25H22N2O2Na 405.1573; Found 405.1575.
N-(3-Phenyl-1-(1-phenyl-1H-pyrrol-2-yl)prop-2-yn-1-yl)benzamide (8g). (Table 2, entry 8):
Following general procedure A, a 10 mL dried Schlenk tube was charged with anhydrous CuCl
(3.0 mg, 0.03 mmol), methanol (1.15 mL) and 5g (59 mg, 0.15 mmol). The reaction was
vigorously stirred at rt for 19 hours. After the usual workꢀup, preparative TLC (hexanes/
CH2Cl2= 1/9) afforded the title compound (37 mg, 65%) as a pale yellow solid; M.p = 112ꢀ115
°C; 1H NMR (250 MHz, CDCl3) δ 7.66ꢀ7.58 (m, 2H), 7.52ꢀ7.27 (m, 13H), 6.86 (dd, 1H, J= 1.9
and 2.8 Hz), 6.65 (dd, 1H, J= 1.8 and 3.5 Hz), 6.41 (d, 1H, J= 8.3 Hz), 6.36 (d, 1H, J= 8.3 Hz),
6.30 (dd, 1H, J=3.0 and 3.5 Hz); 13C NMR (62.5 MHz, CDCl3) δ 165.5, 139.4, 133.8, 131.8,
131.6, 130.2, 129.4, 128.5, 128.4, 128.1, 128.0, 127.0, 126.3, 124.1, 122.6, 109.7, 108.3, 86.9,
83.2, 39.0. HRMS (ESI) m/z: [M+Na+] Calcd for C26H20N2ONa 399.1468; Found 399.1474.
N-(1-(1-Phenyl-1H-pyrrol-2-yl)heptyl)acetamide (8h). (Table 2, entry 9): In accordance with
general procedure B, nitrosobenzene (43 mg, 0.4 mmol) was added to a solution of 4h (42 mg,
0.20 mmol) in CH2Cl2 (0.4 mL) and stirred at rt. The residue was diluted with methanol (1.54
mL) and anhydrous CuCl (4.0 mg, 0.04 mmol) was added. After 24 hours, the usual workꢀup
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 23
1
2
3
4
5
6
7
8
9
afforded a crude mixture that was purified by preparative TLC (hexanes/AcOEt= 7/3) to afford
8h as a pale yellow amorphous solid (26 mg, 46%). 1H NMR (250 MHz, CDCl3) δ 7.28ꢀ7.45 (m,
5H); 6.77 (app t, 1H, J = 2.0 Hz); 6.21ꢀ6.26 (m, 2H); 5.47 (bd, 1H, J = 8.0 Hz, NH); 4.96 (app q,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1H, J = 8.0 Hz); 1.81 (s, 3H); 1.68ꢀ1.75 (m, 2H); 1.20ꢀ1.40 (m, 8H); 0.80ꢀ0.89 (m, 3H); C
NMR (62.5 MHz, CDCl3) δ 168.5, 139.8, 134.4, 129.4, 127.9, 126.5, 123.0, 108.3, 106.6, 46.0,
35.9, 31.6, 29.0, 26.0, 23.0, 22.6, 14.2. HRMS (ESI) m/z: [M+Na+] Calcd for C19H26N2ONa
321.1937; Found 321.1943.
N-(Phenyl(1-phenyl-1H-pyrrol-2-yl)methyl)acetamide (8i). (Table 2, entry 10): In accordance
with general procedure A, a 10 mL dried Schlenk tube was charged with anhydrous CuCl (0.03
mmol, 3.0 mg), methanol (1.15 mL) and bicycle 5i (43 mg, 0.15 mmol). The reaction was
vigorously stirred at room temperature for 16 hours. The usual workꢀup afforded a crude mixture
that was purified by flash chromatography (hexanes/AcOEt= 7/3) to give the title compound as
an amorphous solid (26 mg, 60%). 1H NMR (250 MHz, CDCl3) δ 7.45ꢀ7.11 (m, 10H), 6.83ꢀ6.78
(m, 1H), 6.25ꢀ6.16 (m, 2H), 5.99 (dd, 1H, J = 1.7 and 3.5 Hz), 5.91 (d, 1H, J= 7.7 Hz), 1.87 (s,
3H); 13C NMR (62.5 MHz, CDCl3) δ 168.4, 140.8, 133.4, 132.3, 129.2, 128.3, 127.8, 127.3,
127.0, 126.3, 123.3, 108.9, 108.1, 50.1, 23.0. HRMS (ESI) m/z: [M+Na+] Calcd for
C19H18N2ONa 313.1311; Found 313.1320.
N-(Phenyl(1-phenyl-1H-pyrrol-2-yl)methyl)benzamide (8l). (Table 2, entry 12): In accordance
with general procedure B, nitrosobenzene (43 mg, 0.4 mmol) was added to a solution of 4l (52
mg, 0.20 mmol) in CH2Cl2 (0.4 mL) and stirred at rt. The residue was diluted with methanol
(1.54 mL) and anhydrous CuCl (0.04 mmol, 4.0 mg) was added. After 18 hours, the usual workꢀ
up afforded a crude mixture that was subjected to flash chromatography to give 8l (41 mg, 59%)
1
as a yellow amorphous solid. H NMR (250 MHz, CDCl3) δ 7.68ꢀ7.60 (m, 2H), 7.53ꢀ7.18 (m,
13H), 6.86ꢀ6.81 (m, 1H), 6.53 (d, 1H, J=7.2 Hz), 6.41 (d, 1H, J= 7.8 Hz), 6.24 (t, 1H, J= 3.2 Hz),
20
ACS Paragon Plus Environment

Page 21 of 23
The Journal of Organic Chemistry
1
2
6.09ꢀ6.04 (m, 1H); 13C NMR (62.5 MHz, CDCl3) δ 165.9, 140.8, 139.6, 134.2, 133.3, 131.5,
129.3, 128.5, 128.4, 127.8, 127.4, 127.1, 126.9, 126.3, 123.5, 108.2, 50.6. HRMS (ESI) m/z:
[M+Na+] Calcd for C24H20N2ONa 375.1468; Found 375.1471.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information Available: Text giving detailed experimental procedures and
characterization data for all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■ AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: pineschi@farm.unipi.it
Notes
The authors declare no competing financial interest.
Acknowledgement. This work was supported by the University of Pisa.
REFERENCES
(1) For a recent example, see: Biava, M.; Porretta, G. C.; Supino, S.; Sleiter, G. Curr. Org.
Chem. 2007, 11, 1092ꢀ1112.
(2) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. S., Rees, C. W.,
Scriven, E. F. V. Eds.; Pergamon: Oxford, U.K. 1996, Vol. 2, p 207.
(3) To the best of our knowledge, the Nꢀarylation of pyrrole by aryl halides, catalyzed by
palladium or copper catalysts, has been applied only to unsubstituted pyrroles. For
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 23
1
2
3
4
5
6
7
8
9
examples, see: (a) Ma, H.ꢀC.; Jiang, X.ꢀZ. J. Org. Chem. 2007, 72, 8943ꢀ8946. (b) Antilla,
J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578ꢀ5587. (c)
Hartwig, J. F.; Kawatsura, M.; Hauck, S. H.; Shaughnessy, K. H.; AlcazarꢀRoman, L. M. J.
Org. Chem. 1999, 64, 5575.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) (a) Scheiner, P.; Chapman, O. L.; Lassila, J. D. J. Org. Chem. 1969, 34, 813ꢀ816. (b) Lee,
H. Y.; Choo, D. J. Bull. Korean Chem. Soc. 1993, 14, 423ꢀ424.
(5) (a) Kresze, G.; Braun, H. Tetrahedron Lett. 1969, 10, 1743ꢀ1746. (b) Defoin, A.; Fritz, H.;
Geffroy, G.; Streith, J. Tetrahedron Lett. 1986, 27, 3135ꢀ3138.
(6) Ragaini, F.; Cenini, S.; Brignoli, D.; Gasperini, M.; Gallo, E. J. Org. Chem. 2003, 68, 460ꢀ
466.
(7) Ragaini, F.; Cenini, S.; Borsani, E.; Dompè. M.; Gallo, E.; Moret, M. Organometallics
2001, 20, 3390ꢀ3398.
(8) McClure, K. F.; Danishefky, S. J. J. Org. Chem. 1991, 56, 850ꢀ853.
(9) Calvet, G.; Blanchard, N.; Kouklovsky, C. Synthesis 2005, 3346ꢀ3354.
(10) Crotti, S.; Berti, F.; Pineschi, M. Org. Lett. 2011, 13, 5152ꢀ5155.
(11) Bodnar, B. S.; Miller, M. J. Angew. Chem. Int. Ed. 2011, 50, 5630ꢀ5647.
(12) Lemire, A.; Beaudoin, D.; Grenon, M.; Charette, A. B. J. Org. Chem. 2005, 70, 2368ꢀ
2371.
(13) Keck, G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett. 1995, 36, 7419ꢀ7421.
22
ACS Paragon Plus Environment

Page 23 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
(14) Cesario, C.; Tardibono, Jr. L. P.; Miller, M. J. J. Org. Chem. 2009, 74, 448ꢀ451.
(15) Yang, B.; Miller, M. Org. Lett. 2010, 12, 392ꢀ395.
7
8
9
(16) Dörr, A. A.; Lubell, W. D. J. Org. Chem. 2012, 77, 6414ꢀ6422.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(17) (a) Cativiela, C.; Diaz de Villegas, M. D.; Garcia, J. I.; Mayoral, J. A.; Melendez, E. Bull.
Soc. Chim. Belges 1984, 93, 479ꢀ482. (b) Hodges, L. M.; Gonzales, J.; Koontz, J. I.;
Myersa, W. H.; Harman, W. D. J. Org. Chem. 1995, 60, 2125ꢀ2146.
(18) For a review, see: Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev.
2011, 112, 2642ꢀ2713.
(19) Knaus, E. E.; Redda, K. Can. J. Chem. 1977, 55, 1788ꢀ1791.
(20) Kurita, J.; Iwata, K.; Sakai, H.; Tsuchiya, T. Chem. Pharm. Bull. 1985, 33, 4572ꢀ4580.
(21) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107ꢀ1110.
(22) Giam, C. S.; Knaus, E. E. Tetrahedron Letters 1971, 52, 4961ꢀ4964.
(23) Knaus, E. E.; Avasthi, K.; Giam, C. S. Can. J. Chem. 1980, 58, 2447ꢀ2451.
(24) Augelmann, G.; Streith, J.; Fritz, H. Helv. Chim. Acta 1985, 68, 95ꢀ103.
(25) Yamaguchi, R.; Nakazono, Y.; Kawanisi, M. Tetrahedron Lett. 1983, 24, 1801ꢀ1804.
(26) Giam, C. S.; Knaus, E.; Pasutto, F. M. J. Org. Chem. 1974, 39, 3565ꢀ3568.
23
ACS Paragon Plus Environment