Regioselectivity of the 1,3-Dipolar Cycloaddition of Organic Azides to 7-Heteronorbornadienes. Synthesis of β-Substituted Furans/Pyrroles

Article abstract of DOI:10.1021/acs.joc.0c00810

An efficient procedure for the preparation of β-substituted furans/pyrroles is presented. The methodology is based on the use of 7-oxa/azanorbornadienes as dipolarophiles in 1,3-dipolar cycloaddition with benzyl azide. The triazoline cycloadduct thus form

Full text of DOI:10.1021/acs.joc.0c00810

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Article
Regioselectivity of the 1,3-dipolar cycloaddition of organic azides to
7-heteronorbornadienes. Synthesis of #-substituted furans/pyrroles
Enrique Gil de Montes, Macarena Martínez-Bailén, Ana T.
Carmona, Inmaculada Robina, and Antonio J. Moreno-Vargas
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00810 • Publication Date (Web): 10 Jun 2020
Downloaded from pubs.acs.org on June 13, 2020
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Regioselectivity of the 1,3-dipolar cycloaddition of organic azides to 7-heteronorbornadienes.
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Synthesis of β-substituted furans/pyrroles
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Enrique Gil de Montes, Macarena Martínez-Bailén, Ana T. Carmona, Inmaculada Robina and
Antonio J. Moreno-Vargas*
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Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, C/ Prof. García
González, 1, 41012-Sevilla (Spain). Email: ajmoreno@us.es.
Abstract
An efficient procedure for the preparation of β-substituted furans/pyrroles is presented. The
methodology is based on the use of 7-oxa/azanorbornadienes as dipolarophiles in a 1,3-dipolar
cycloaddition with benzyl azide. The triazoline cycloadduct thus formed spontaneously
decomposes via a retro-Diels-Alder (rDA) reaction to afford a β-substituted furan/pyrrole
derivative and a stable triazole. The scope of this tandem 1,3-dipolar cycloaddition/rDA reaction
was studied with thirteen 7-heteronorbornadienes. This study allowed a deep knowledge of the
regioselectivity of the reaction which can be tuned through the substituents of the
heteronorbornadienic systems.
Graphical abstract
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Introduction
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Furan and pyrrole motifs are present in many natural products,1 synthetic materials2 and
pharmaceuticals.3 Additionally, they are also important reaction intermediates in the
preparation of innovative porphyrin dye-sensitized solar cells4 and biologically relevant
compounds.5 Due to this interest, the development of new methodologies/strategies for the
synthesis of β-substituted pyrroles and furans still constitutes an active field in organic
chemistry, with relevant publications in the last years.6 This synthesis still remains a challenge
as most reported procedures imply multi-step routes or sophisticated methods.7 Particularly, β-
halo-furans and pyrroles are important intermediates for further functionalization via C-C, C-N
or C-S bond forming reactions.8,9,10,11 Taking into account that the direct electrophilic
substitution on pyrrole leads to the α-substituted regioisomer as major compound,12 it is
necessary to block the α-position or to introduce a bulky group at the nitrogen atom to achieve
the β-substitution. In any case, the use of blocking or directing groups requires derivatization
steps that clearly reduces the synthetic efficiency of the route. A similar problem is found in the
preparation of β-substituted furans due to the tendency of furans to undergo both metallation
and electrophilic reactions at α-position.13
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7-Heteronorbornadienes (7-heterobicyclo[2.2.1]hepta-2,5-dienes) are systems with a unique
geometry that provokes the accumulation of ring strain energy.14 Double bonds embedded into
[2.2.1]bicyclic systems are well known to easily react in cycloaddition reactions.15 Our research
group has recently used this strategy with azanorbornadienes for protein bioconjugation
purposes.16 In accordance to Houk’s studies on norbornene systems, the strain results in a
predistortion of the alkene, which resembles the transition state geometry of the
cycloaddition.17 This reduces the distortion energy gap to achieve the transition state leading to
accelerated reactions. 1,3-Dipolar cycloadditions between (7-hetero)norbornadienes and
different dipoles such as nitrile oxides, nitrile imines and azides have been previously
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described.18,19,20,21,22 Organic azides are not as reactive 1,3-dipoles as nitrile oxides or nitrile
imines; on the contrary, they are stable molecules that do not need to be in situ synthesized. 7-
Heteronorbornadienes are easily prepared by Diels-Alder reaction between an electron-
deficient alkyne and a furan or pyrrole derivative.23 It has been reported that the 1,3-dipolar
cycloaddition between organic azides and 7-heteronorbornadienes as dipolarophiles can follow
two different reaction pathways depending on the site-selective attack of the dipole.19 On the
basis of the frontier orbital theory, the dipole will use its HOMO for the interaction with the
LUMO of the bicyclic dipolarophile, which is mainly24 localized on the electron-deficient alkene
(Scheme 1, path A). Alternatively, the dipole can use its LUMO for the interaction with the HOMO
of the bicyclic system, which is mainly localized on the electron-rich alkene (Scheme 1, path B).
In both cases, the 1,3-dipolar cycloaddition will generate unstable triazoline intermediates that
decompose via a retro-Diels-Alder (rDA) reaction to afford the corresponding stable triazole and
furan or pyrrole derivatives.
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Scheme 1. Proposed reaction pathways for the 1,3-cycloaddition of organic azides to 7-
heteronorbornadienes. Path A was always the main pathway in all these previously reported examples.
This tandem 1,3 dipolar cycloaddition-rDA reaction has been explored especially in 7-
oxanorbornadienes,20,22,25 with only a couple of examples in 7-azanorbornadienes.21,26 In all the
reported examples with 7-oxa/azanorbornadienes, path A was the main (or unique) pathway for
the reaction. The sequence via path A has been exploited by Rutjes and coworkers as an
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interesting strategy for metal-free triazole-based protein bioconjugation that has been used in
further biological applications.22 Nevertheless, an exhaustive study of the site-selectivity of this
cycloaddition tuning the electronic density of the electron-deficient double bond has not been
previously reported. The exploration of the reaction conditions and the substituents on the
bicyclic systems that could favour path B is an interesting goal, as this constitutes an efficient
strategy for the preparation of β-substituted furans/pyrroles.
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Results and discussion.
7-Oxa- and 7-azanorbornadienes 2a-d and 3a-e (Scheme 2) can be easily synthesized by Diels-
Alder (DA) reaction between furan/N-Boc-pyrrole and electron-deficient alkynes (commercially
available or easily prepared from commercial alkyne precursors). The Boc group, instead of
other acyl groups, was chosen in order to ensure the dienic behaviour of this heterocycle. In
most of the cases, the electron-deficient character of the alkyne allowed the DA be efficient,
leading to the final cycloadducts in moderate-to-good yields.27 However, DA reaction with
alkynes containing the ethoxycarbonyl group, which is a weaker electron-deficient group than
tosyl, led to the corresponding products in poor yield. Thiovinyl derivatives 2f,g and 3f,g can be
easily obtained after substitution reaction of cycloadducts 2c,d and 3c,d with N-Boc-cysteamine
under basic conditions.
Scheme 2. Synthesis of differently substituted 7-heteronorbornadienes.
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All these 7-heteronorbornadienes were assayed in the 1,3-dipolar cycloaddition with benzyl
azide (Table 1). For comparative purposes, some representative examples of the bibliography
were also included in the table (entries 13, 22, 23).
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Table 1. Regioselectivity of the 1,3-dipolar cycloaddition between 7-heteronorbornadienes and benzyl
azide.
Entry
Bicyclic
system
X
R1
R2
Solvent
T
(°C)
t (h)
Paths A:B
(%)[a]
Yield (%)[b]
heterocycle
4 or 5
Pyrrole 6
(% N-Boc
deprotection)[c]
-
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2
2a
2b
2c
2c
2c
2d
2d
2d
2f
N-Boc
N-Boc
N-Boc
N-Boc
N-Boc
N-Boc
N-Boc
N-Boc
N-Boc
N-Boc
N-Boc
N-Boc
N-Boc
O
Ts
Ts
H
Cl
Toluene
Toluene
Toluene
DMF
110
110
110
110
65
1
2
74:26
7:93
19
66
54
-
28
34
100
70
9
3
Ts
Br
3
5:95
4
Ts
Br
1
11:89
17:83
22:78
20:80
29:71
27:73
4:96
5
Ts
Br
MeOH
7
-
6
COOEt
COOEt
COOEt
Ts
Br
Toluene
DMF
110
110
65
3
59
-
7
Br
1
100
48
19
1
8
Br
MeOH
7
35
53
86
91
78
-
9
SR4[f]
SR4[f]
SR4[f]
SR4[f]
Toluene
Toluene
Toluene
Toluene
CD3OD
110
70
1
10
11
12
13[d]
14
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16
17
18
19
2f
Ts
10
58
2
2f
Ts
50
0:100
0:100
100:0
84:16
15:85
15:85
30:70
9:91
0
2g
2h
3a
3b
3c
3d
3e
3e
COOEt
110
25
0
COOMe COOMe
14
1
-
Ts
Ts
H
Cl
Br
Br
I
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
110
110
110
110
110
70
-
-
O
1
85
80
63
81
-
-
O
Ts
1
-
-
O
COOEt
Ts
1
O
1
-
-
O
Ts
I
5
9:91
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3f
3g
3h
3i
O
O
O
O
Ts
SR4[f]
SR4[f]
CF3
Toluene
Toluene
CD3OD
CD3OD
110
110
25
1
1
-
0:100
0:100
97:3
90
92
-
-
-
-
-
COOEt
COOEt
22[e]
23[e]
COOMe COOMe
25
-
95:5
-
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[a]Path A/Path B ratio determined by 1H-NMR analysis of the reaction mixtures. The conversion of the substrates was
quantitative in all cases. The amount of unprotected pyrrole 6 is incorporated as part of path B. [b] The yield of the β-
substituted furan/N-Boc-pyrrole after isolation and chromatographic purification is given (except when indicated).
1
[c]% N-Boc deprotection measured by H-NMR is given. [d]See ref. 26. [e]See ref. 22b. [f]R4 = -CH2CH2NHBoc. -: not
determined/not given/not isolated.
All the heteronorbornadiene systems reacted completely with benzyl azide in toluene at 110 °C
after 1-3 h. With the exceptions of vinyl sulfones 2a and 3a (entries 1 and 14), in all the cases
path B was the major pathway of the reaction. The presence of O or N-Boc in the bridge did not
significantly affect the regioselectivity of the 1,3-dipolar cycloaddition, being the azabicylic
systems slightly more prone to react by the path B than the corresponding oxa-analogues
(entries 1-3 vs entries 14-16). The solvent did not show significant influence on the
regioselectivity (entries 3-5 and 6-8), but showed to be crucial on the yield of the final N-
protected β-substituted pyrroles 4. N-Boc-pyrrole derivatives 4 are completely or significantly
converted to the corresponding unprotected derivatives 6 in DMF (entries 4 and 7) and MeOH
(entries 5 and 8). For this reason, toluene was chosen as solvent for most of the experiments.28
The presence of a heteroatom instead of H at C-3 of the bicyclic system, allows electron donation
to the electron-poor double bond of the system. This electronic effect increases the energy of
the LUMO, which is mainly located on the electron-poor deficient alkene, being detrimental for
its interaction with the HOMO of the dipole (path A). Instead, the interaction between the
HOMO of the bicyclic system and the LUMO of the azide (path B) turns into the best option. In
this sense, all the heteronorbornadiene derivatives containing an halogen at C-3 reacted in the
same way, favouring clearly path B over path A (entries 2-5, 6-8, 15-19). A steric influence on
the regioselectivity of the reaction should not be discarded, as the size of the halogen atom at
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C-3 increases simultaneously with the ability to release electronic density to the π-system of the
bicycle. Nevertheless, the electronic effect prevails over the steric one as it is observed for the
bicyclic system 3h with a trifluoromethyl substituent at C-3 (Table 1, entry 22). The
trifluoromethyl group exhibits a larger steric demand than a Br or Cl group,29 however this fact
did not lead to a predominance of path B over path A as it would have been expected from a
steric point of view. This behaviour can be justified by electronic effects because this group, that
exhibits an important inductive electron-withdrawing effect, is not able to release electronic
density to the π-system of the bicycle. A similar effect is observed for the examples previously
reported in the bibliography, where C-3 is substituted with the methoxycarbonyl group (entries
13 and 23). In this sense, we expected to observe the higher path B/A ratio for dipolarofiles 2f,g
and 3f,g that contain a thioether function on C-3, as a consequence of the ability of the sulfur
atom to donate electrons to the contiguous π-system. In fact, path B was the only one found for
reactions with 2g, 3f and 3g (entries 12, 20 and 21). Surprisingly, for dipolarophile 2f, the
regioselectivity was not as high as expected (path A/B: 27/73, entry 9) under the same reaction
conditions and even lower than with halogenated azanorbornadienes 2b and 2c (entries 2 and
3). A possible explanation for these results is that a simultaneous retro-Diels-Alder (rDA) reaction
of 2f that could compete with the 1,3-dipolar cycloaddition could take place (Scheme 3). The
resulting alkyne of this collateral reaction (compound 10) could directly react with the benzyl
azide through a Huisgen cycloaddition to give the regioisomeric 4,5-disubstituted triazoles 8f
and 9f, what would distort the real path A/B ratio. This hypothesis was explored with the
heteronorbornadienes where path A was observed [heteronorbornadiene (% path A):
azanorbornadienes 2a (74%), 2b (7%), 2c (5-17%), 2d (22 -29%), 2f(2-27%); oxanorbornadienes
3a (84%), 3b,c (15%), 3d (30%), 3e (9%)]. The major part of these bicyclic systems was stable
under refluxing toluene in the period of time needed for the 1,3-dipolar cycloaddition (1-3h).
However, partial rDA was detected for oxanorbornadiene 3e (8% rDA after 1h) and, especially,
for azanorbornadiene 2f (76% rDA after 1 h) (Scheme 3). To confirm the competition of the
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Huisgen cycloaddition after the rDA reaction, alkyne 1e was made react with benzyl azide in
toluene at 110 °C. Regioisomeric triazoles 8e and 9e were obtained in 1 h after complete
conversion. This experiment could not be carried out in the case of 10 because this alkyne could
not be isolated nor synthesized separately.
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Scheme 3. Collateral rDA reaction of 2f and 3e and subsequent Huisgen cycloaddition.
With these results in hand, we decided to perform the 1,3-dipolar cycloaddition in toluene with
2f and 3e at lower temperature (entries 10, 11 and 19), in order to avoid the collateral rDA. At
70 °C, the extension of the rDA was clearly slowed down in the case of 2f (4% conversion after
4h) and abolished for 3e (no rDA was detected after 4h). To our delight, at 70 °C the 1,3-dipolar
cycloaddition between 2f and benzyl azide, although considerably slower, was clearly more
regioselective than at 110 °C (entry 9 vs entry 10). At the same temperature, in the case of 3e
the regioselectivity was not improved (entries 18 and 19, highly regioselective for both 110° and
70 °C), what indicates that in this case the effect of the rDA should not be really significant. At
50 °C, the 1,3-dipolar cycloaddition between 2f and benzyl azide showed total regioselectivity
(entry 11).
In summary, in this work we have demonstrated that the regioselectivity of the 1,3-dipolar
cycloaddition between 7-heteronorbornadienes and benzyl azide can be efficiently controlled
by tuning the electronic density of the electron-poor double bond of the bicyclic system. The
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bicyclic dipolarophile promoted a spontaneous rDA reaction of the intermediate cycloadducts
that directly afforded functionalized furans or pyrroles. Thus, the synthetic sequence that
implies a Diels-Alder reaction between electron-poor alkynes and furan/N-Boc-pyrrole, followed
by a 1,3-dipolar cycloaddition of the resulting heteronorbornadiene with benzyl azide, showed
to be a versatile approach for the preparation of β-substituted furans and pyrroles. In particular,
this methodology constitutes an efficient strategy for the synthesis of β-halo-furans and
pyrroles. Altogether, this sequence allows the incorporation of the substituents previously
present in the initial alkyne to the β-positions of a furan or pyrrole.
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Experimental section
General methods
Infrared spectra were recorded with a Jasco FTIR-410 spectrophotometer. 1H- and 13C{1H}-NMR
spectra were recorded with a Bruker AMX300 spectrometer for solutions in CDCl3, CD3OD and
DMSO-d6. δ are given in ppm and J in Hz. J are assigned and not repeated. All the assignments
were confirmed by 2D spectra (COSY and HSCQ). HMBC and NOE experiments were performed
when necessary. High resolution mass spectra were recorded on a Orbitrap Elite spectrometer
with an ion trap mass analyser. For reactions that require heating, aluminium heating blocks
with magnetic stirring were used. TLC was performed on silica gel 60 F254 (Merck), with detection
by UV light charring with p-anisaldehyde and KMnO4. Silica gel 60 (Merck, 40-60 and 63-200 μm)
was used for preparative chromatography.
[2-(Iodo)ethynyl] p-tolyl sulfone (1e). To
a solution of commercial p-tolyl [2-
(trimethylsilyl)ethynyl] sulfone (1.54 g, 6.11 mmol) in acetone (45 mL), N-iodosuccinimide (1.59
g, 6.72 mmol) and AgNO3 (104 mg, 0.611 mmol) were added in darkness. After stirring for 1.5 h
at r.t., the mixture was filtered through celite and the solvent removed under reduced pressure.
The resulting residue was purified by chromatography column on silica gel (EtOAc:cyclohexane
1:5) to give 1e (1.72 g, 5.61 mmol, 92%) as a white solid. IR (ῡ) 2922, 2118 (C≡C), 1593, 1323,
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1083, 795 cm-1. H-NMR (300 MHz, CDCl3)  7.90-7.86 (m, 2H, H-Ar), 7.40-7.37 (m, 2H, H-Ar),
2.47 (s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4 MHz, CDCl3)  146.0 (Cq-Ar), 138.1 (Cq-Ar), 130.3, 127.8
(C-Ar), 92.0 (Cq of alkyne), 23.9 (Cq of alkyne), 21.9 (CH3 of Ts). HRESIMS m/z found 328.9101
calcd. for C9H7IO2NaS (M+Na)+: 328.9104.
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(rac)-(1R,4S)-N-Boc-2-chloro-3-tosyl-7-azabicyclo[2.2.1]hepta-2,5-diene (2b). To a solution of
alkyne 1b30 (309 mg, 1.44 mmol) in toluene (2 mL), commercial N-Boc-pyrrole (1.2 mL, 7.2 mmol)
o
was added and the reaction mixture was stirred at 80 C for 1 d. Then, the solvent was
evaporated and the resulting residue was purified by chromatography column on silica gel
(EtOAc:cyclohexane 1:8) to give 2b (381 mg, 0.998 mmol, 69%) as a yellow oil. IR (ῡ) 2984, 1718
(C=O), 1581, 1318, 1154, 828 cm-1. 1H-NMR (300 MHz, DMSO-d6, 353 K)  7.77-7.73 (m, 2H, H-
Ar), 7.50-7.47 (m, 2H, H-Ar), 7.11-7.06 (m, 2H, H-5, H-6), 5.32 (td, 1H, JH,H = 2.3, JH,H = 1.1, H-1 or
H-4), 5.11 (td, 1H, JH,H = 2.3, JH,H = 1.0, H-4 or H-1), 2.43(s, 3H, CH3 of Ts), 1.30 (s, 9H, -C(CH3)3).
13C{1H}-NMR (75.4 MHz, DMSO-d6, 353 K)  156.6, 146.7 (C-2, C-3), 152.8 (C=O, Boc), 144.8 (Cq-
Ar), 142.7, 139.2 (C-5, C-6), 135.7 (Cq-Ar), 129.8, 126.9 (C-Ar), 80.9 (-C(CH3)3), 73.4, 68.7 (C-1, C-
4), 27.2 (-C(CH3)3), 20.6 (CH3 of Ts). HRESIMS m/z found 404.0691 calcd. for C18H20ClNO4NaS
(M+Na)+: 404.0694.
(rac)-(1R,4S)-2-Chloro-3-tosyl-7-oxabicyclo[2.2.1]hepta-2,5-diene (3b). To a solution of alkyne
1b30 (312 mg, 1.45 mmol) in toluene (3 mL), furan (1.3 mL, 18 mmol) was added and the reaction
mixture was stirred at 45 oC for 1 d. Then, the solvent was evaporated and the resulting residue
was purified by chromatography column on silica gel (EtOAc:cyclohexane 1:5) to give 3b (350
1
mg, 1.24 mmol, 86%) as a brown solid. IR (ῡ) 2925, 1587, 1329, 1149, 870 cm-1. H-NMR (300
MHz, CDCl3)  7.79-7.75 (m, 2H, H-Ar), 7.37-7.34 (m, 2H, H-Ar), 7.10-7.05 (m, 2H, H-5, H-6), 5.59-
5.58 (m, 1H, H-1 or H-4), 5.25 (ap. t, 1H, H-4 or H-1), 2.45 (s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4
MHz, CDCl3)  157.7, 146.8 (C-2, C-3), 145.4 (Cq-Ar), 144.3, 140.2 (C-5, C-6), 136.4 (Cq-Ar), 130.2,
127.8 (C-Ar), 88.9, 85.0 (C-1, C-4), 21.8 (CH3 of Ts). HRESIMS m/z found 305.0009 calcd. for
C13H11ClO3NaS (M+Na)+: 305.0010.
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(rac)-(1R,4S)-2-Iodo-3-tosyl-7-oxabicyclo[2.2.1]hepta-2,5-diene (3e). To a solution of 1e (305
mg, 0.996 mmol) in toluene (2 mL), furan (0.88 mL, 12 mmol) was added and the reaction
mixture was stirred at 45 oC for 1 d. Then, the solvent was evaporated and the resulting residue
was purified by chromatography column on silica gel (EtOAc:cyclohexane 1:4→1:2) to give 3e
(362 mg, 0.968 mmol, 97%) as a pale yellow solid. IR (ῡ) 2920, 1547, 1306, 1146, 874 cm-1. 1H-
NMR (300 MHz, CDCl3)  7.80-7.77 (m, 2H, H-Ar), 7.36 (d, 2H, JH,H = 8.0, H-Ar), 7.06 (dd, 1H, JH,H
= 5.3, JH,H = 1.8, H-5 or H-6), 6.98 (dd, 1H, JH,H = 5.3, JH,H = 1.8, H-6 or H-5), 5.51 (ap. t, 1H, H-1 or
H-4), 5.47 (ap. t, 1H, H-4 or H-1), 2.44 (s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4 MHz, CDCl3)  157.0,
(C-3), 145.4 (Cq-Ar), 143.1, 140.4 (C-5, C-6), 135.9 (Cq-Ar), 130.2, 127.9 (C-Ar), 117.5 (C-2), 94.1,
84.9 (C-1, C-4), 21.9 (CH3 of Ts). HRESIMS m/z found 396.9361 calcd. for C13H11IO3NaS (M+Na)+:
396.9366.
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(rac)-(1R,4S)-N-Boc-2-[(2-(N-Boc-amino)ethyl)thio]-3-tosyl-7-azabicyclo[2.2.1]hepta-2,5-
diene (2f). To a solution of azabicycle 2c27d (241 mg, 0.566 mmol) in THF (1 mL), a solution of N-
Boc-cysteamine (84 mg, 0.47 mmol) in THF (1.4 mL), K2CO3 (198 mg, 1.42 mmol, in three
portions, one portion every 30 minutes) and H2O (0.8 mL) were added. After stirring for 1.5 h at
r.t., the reaction mixture was diluted with CH2Cl2 and the organic phase was washed twice with
H2O and brine. The resulting organic phase was dried over Na2SO4, filtered and evaporated.
Chromatographic purification on silica gel (EtOAc:cyclohexane 1:3) afforded 2f (202 mg, 0.386
mmol, 82%) as a pale yellow solid. IR (ῡ) 3378 (NH), 2979, 1706 (C=O), 1519, 1253, 1148, 871
cm-1. 1H-NMR (300 MHz, DMSO-d6, 353 K)  7.72-7.68 (m, 2H, H-Ar), 7.42 (d, 2H, JH,H = 8.1, H-Ar),
6.99-6.96 (m, 1H, H-5 or H-6), 6.93-6.90 (m, 1H, H-6 or H-5), 6.83 (bs, 1H, NH), 5.61 (ap. t, 1H, H-
1 or H-4), 5.23-5.21 (m, 1H, H-4 or H-1), 3.33-3.03 (m, 4H, -CH2CH2NHBoc), 2.41 (s, 3H, CH3 of
Ts), 1.42 (s, 9H, -C(CH3)3), 1.27 (s, 9H, -C(CH3)3). 13C{1H}-NMR (75.4 MHz, DMSO-d6, 353 K)  166.7
(C-2), 155.1, 152.7 (C=O, Boc), 143.7 (Cq-Ar), 142.0, 138.5 (C-5, C-6), 139.1 (C-3), 137.1 (Cq-Ar),
129.4, 126.3 (C-Ar), 80.5, 77.8 (-C(CH3)3), 70.3, 68.5 (C-1, C-4), 40.7 (-CH2CH2NHBoc), 31.2 (-
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CH2CH2NHBoc), 27.8, 27.2 (-C(CH3)3), 20.6 (CH3 of Ts). HRESIMS m/z found 545.1751 calcd. for
C25H34N2O6NaS2 (M+Na)+: 545.1750.
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azabicyclo[2.2.1]hepta-2,5-diene (2g). This compound was synthesized following the previous
procedure described for 2f, using azabicycle 2d27b (119 mg, 0.346 mmol) as starting material.
Chromatographic purification on silica gel (EtOAc:cyclohexane 1:4) afforded 2g (108 mg, 0.245
mmol, 85%) as a pale yellow oil. IR (ῡ) 3369 (NH), 2978, 1687 (C=O), 1507, 1366, 1161, 729 cm-
1. 1H-NMR (300 MHz, DMSO-d6, 353K)  7.13-7.08 (m, 2H, H-5, H-6), 6.81 (bs, 1H, NH), 5.56 (bs,
1H, H-1 or H-4), 5.31 (td, 1H, JH,H = 2.1, JH,H = 1.1, H-4 or H-1), 4.21-4.09 (m, 2H, -CH2CH3), 3.35-
3.10 (m, 4H, -CH2CH2NHBoc), 1.42 (s, 9H, -C(CH3)3), 1.37 (s, 9H, -C(CH3)3), 1.23 (t, 3H, JH,H = 7.1, -
CH2CH3). 13C{1H}-NMR (75.4 MHz, DMSO-d6, 353K)  169.2 (C-2), 162.4 (C=O, COOEt), 155.1,
153.1 (C=O, Boc), 142.8, 140.0 (C-5, C-6), 132.1 (C-3), 80.0, 77.7 (-C(CH3)3), 69.4, 67.4 (C-1, C-4),
59.2 (-CH2CH3), 40.9 (-CH2CH2NHBoc), 31.0 (-CH2CH2NHBoc), 27.8, 27.4 (-C(CH3)3), 13.8 (-CH2CH3).
HRESIMS m/z found 463.1871 calcd. for C21H32N2O6NaS (M+Na)+: 463.1873.
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(rac)-(1R,4S)-2-[(2-(N-Boc-amino)ethyl)thio]-3-tosyl-7-oxabicyclo[2.2.1]hepta-2,5-diene (3f).
This compound was synthesized following the previous procedure described for 2f, using
oxabicycle 3c27d (240 mg, 0.733 mmol) as starting material. Chromatographic purification on
silica gel (EtOAc:cyclohexane 1:2) afforded 3f (216 mg, 0.511 mmol, 84%) as a pale yellow solid.
IR (ῡ) 3379 (NH), 2979, 1702 (C=O), 1523, 1251, 1147, 881 cm-1. 1H-NMR (300 MHz, CDCl3)  7.73
(d, 2H, JH,H = 8.3, H-Ar), 7.32 (d, 2H, H-Ar), 6.99-6.93 (m, 2H, H-5, H-6), 5.78 (bs, 1H, H-4), 5.51
(bs, 1H, H-1), 5.00 (bs, 1H, NH), 3.39-3.23 (m, 2H, -CH2CH2NHBoc), 3.18-2.99 (m, 2H, -
CH2CH2NHBoc), 2.42 (s, 3H, CH3 of Ts), 1.43 (s, 9H, -C(CH3)3). 13C{1H}-NMR (75.4 MHz, CDCl3) 
165.9 (C-2), 155.9 (C=O, Boc), 144.6 (Cq-Ar), 143.6, 139.7 (C-5, C-6), 140.5 (C-3), 137.3 (Cq-Ar),
130.0, 127.2 (C-Ar), 86.5 (C-4), 85.1 (C-1), 80.1 (-C(CH3)3), 41.7 (-CH2CH2NHBoc), 32.3 (-
CH2CH2NHBoc), 28.5 (-C(CH3)3), 21.8 (CH3 of Ts). HRESIMS m/z found 446.1060 calcd. for
C20H25NO5NaS2 (M+Na)+: 446.1066.
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(rac)-(1R,4S)-2-[(2-(N-Boc-amino)ethyl)thio]-3-ethoxycarbonyl-7-oxabicyclo[2.2.1]hepta-2,5-
diene (3g). This compound was synthesized following the previous procedure described for 2f,
using oxabicycle 3d27e (175 mg, 0.714 mmol) as starting material. Chromatographic purification
on silica gel (EtOAc:cyclohexane 1:4) afforded 3g (182 mg, 0.533 mmol, 89%) as a colorless oil.
IR (ῡ) 3361 (NH), 2979, 1682 (C=O), 1507, 1366, 1270, 878 cm-1. 1H-NMR (300 MHz, CDCl3)  7.16
(dd, 1H, J6,5 = 5.4, J6,1 = 1.7, H-6), 7.09 (dd, 1H, J5,4 = 1.8, H-5), 5.74-5.71 (m, 2H, H-1, H-4), 4.99
(bs, 1H, NH), 4.27-4.11 (m, 2H, -CH2CH3), 3.38-3.31 (m, 2H, -CH2CH2NHBoc), 3.20-3.03 (m, 2H, -
CH2CH2NHBoc), 1.44 (s, 9H, -C(CH3)3), 1.29 (t, 3H, JH,H = 7.1, -CH2CH3). 13C{1H}-NMR (75.4 MHz,
CDCl3)  169.2 (C-2), 163.7 (C=O, COOEt), 155.9 (C=O, Boc), 144.6 (C-6), 140.8 (C-5), 133.9 (C-3),
85.7, 84.5 (C-1, C-4), 80.0 (-C(CH3)3), 60.4 (-CH2CH3), 41.7 (-CH2CH2NHBoc), 32.2 (-CH2CH2NHBoc),
28.5 (-C(CH3)3), 14.5 (-CH2CH3). HRESIMS m/z found 364.1188 calcd. for C16H23NO5NaS (M+Na)+:
364.1189.
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General procedure for the 1,3-dipolar cycloaddition between 7-heteronorbornadienes and
benzyl azide. To a solution of the corresponding 7-heteronorbornadiene (1.0 eq) in the solvent
indicated for each case (Table 1), a solution of benzyl azide (1.5 eq) in the same solvent was
added (final concentration: 0.23 M). The reaction was stirred at the desired temperature for the
time indicated for each assay and the solvent was removed under reduced pressure. The crude
reaction mixture was then analysed by 1H-NMR (Figures S1 and S2, Supporting information) and
purified by chromatography column on silica gel to afford the corresponding furan/N-Boc-
pyrrole derivatives 4 or 5. Unprotected pyrroles 6, triazoles 7, 8 and 9 could be isolated only in
the cases where the estimated amount of these product was appreciable (≥10 mg).
1,3-Dipolar cycloaddition of 2a with benzyl azide (Table 1, entry 1).
Following the general procedure and starting from 2a27a (100 mg, 0.29 mmol)
in toluene for 1 h at 110 oC, pyrrole 4a (18 mg, 0.056 mmol, 19%, brown oil)
and triazoles 8a (54 mg, 0.17 mmol, 58%, brown solid) and 9a (13 mg, 0.042
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mmol, 14%, brown solid) were isolated after chromatographic purification
(EtOAc:cyclohexane 1:10→1:5→1:1).
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Data for 4a: IR (ῡ) 3170, 2980, 1752 (C=O), 1594, 1536, 1086, 974, 820 cm-1. 1H-NMR (300 MHz,
CDCl3)  7.84-7.82 (m, 2H, H-Ar), 7.79-7.78 (m, 1H, H-2 or H-4 or H-5) 7.31-7.28 (m, 2H, H-Ar),
7.23-7.21 (m, 1H, H-2 or H-4 or H-5), 6.45-6.43 (m, 1H, H-2 or H-4 or H-5), 2.40 (s, 3H, CH3 of Ts),
1.59 (s, 9H, -C(CH3)3). 13C{1H}-NMR (75.4 MHz, CDCl3)  147.6 (C=O, Boc ), 144.0 (Cq-Ar), 139.6
(Cq-Ar), 129.9 (C-Ar), 129.2 (Cq-Ar), 127.4, 123.4, 122.0, 110.3 (C-Ar), 86.0 (-C(CH3)3), 28.0 (-
C(CH3)3), 21.7 (CH3 of Ts). HRESIMS m/z found 344.0920, calcd. for C16H19NO4NaS (M+Na)+:
344.0927.
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Data for 8a: IR (ῡ) 2922, 2851, 1598, 1099, 969, 858, 651 cm-1. 1H-NMR (300 MHz,
CDCl3)  8.09 (s, 1H, H-4), 7.50-7.47 (m, 2H, H-Ar), 7.27-7.21 (m, 3H, H-Ar), 7.14-
7.12 (m, 2H, H-Ar), 7.06-7.04 (m, 2H, H-Ar), 5.82 (s, 2H, CH2Ph), 2.36 (s, 3H, CH3 of
Ts). 13C{1H}-NMR (75.4 MHz, CDCl3) δ 145.8 (Cq-Ar), 137.8 (C-4), 137.6, 136.4, 133.9 (Cq-Ar),
130.1, 128.9, 128.5, 127.8, 127.7 (C-Ar), 53.3 (CH2Ph), 21.8 (CH3 of Ts). HRESIMS m/z found
336.0781, calcd. for C16H15N3O2NaS (M+Na)+: 336.0777.
Data for 9a: 1H-NMR (300 MHz, CDCl3)  7.97 (bs, 1H, H-Ar), 7.95-7.92 (m, 2H, H-Ar), 7.41-7.37
(m, 3H, H-Ar), 7.33-7.27 (m, 4H, H-Ar), 5.52 (s, 2H, CH2Ph), 2.41 (s, 3H, CH3 of Ts).
Its spectroscopic data are in accordance with those described in the
bibliography.31
1,3-Dipolar cycloaddition of 2b with benzyl azide (Table 1, entry 2).
Following the general procedure and starting from 2b (150 mg, 0.393 mmol)
in toluene for 2 h at 110 oC, pyrrole 4b (92 mg, 0.26 mmol, 66%) was isolated
after chromatographic purification (EtOAc:cyclohexane 1:5) as a yellow oil.
Unprotected pyrrole 6b was detected, but could not be isolated. This
compound was prepared separately following the general procedure: A
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solution of the corresponding β-substituted N-Boc-pyrrole (4b in this case,
81 mg, 0.23 mmol) in MeOH (final concentration: 0.08 M) was refluxed for
24 h. Then, the solvent was removed under reduced pressure and the
resulting crude product was purified by chromatography column on silica gel
(EtOAc:cyclohexane 1:1) to give pure 6b (58 mg, 0.23 mmol, quant.) as a
white solid.
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Data for 4b: IR (ῡ) 2981, 1759 (C=O), 1532, 1325, 1251, 812 cm-1. H-NMR (300 MHz, CDCl3) 
7.91-7.87 (m, 2H, H-Ar), 7.86 (d, 1H, JH,H = 2.7, H-2 or H-5), 7.32-7.29 (m, 2H, H-Ar), 7.18 (d, 1H,
H-5 or H-2), 2.41 (s, 3H, CH3 of Ts), 1.59 (s, 9H, -C(CH3)3). 13C{1H}-NMR (75.4 MHz, CDCl3)  146.7
(C=O, Boc), 144.5, 138.3 (Cq-Ar), 129.8, 128.0 (C-Ar), 126.5 (Cq-Ar), 124.4, 119.7 (C-2, C-5), 113.3
(Cq-Ar), 86.8 (-C(CH3)3), 27.9 (-C(CH3)3), 21.7 (CH3 of Ts). HRESIMS m/z found 378.0530, calcd. for
C16H18ClNO4NaS (M+Na)+: 378.0537.
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Data for 6b: IR (ῡ) 3309 (NH), 2919, 1527, 1289, 1142, 810 cm-1. H-NMR (300 MHz, CD3OD) 
7.82 (d, 2H, JH,H = 8.3, H-Ar), 7.44 (d, 1H, JH,H = 2.4, H-2 or H-5), 7.33 (d, 2H, H-Ar), 6.83 (d, 1H, H-
5 or H-2), 2.38 (s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4 MHz, CD3OD)  145.3, 140.9 (Cq-Ar), 130.6,
128.4 (C-Ar), 125.1, 120.2 (C-2, C-5), 122.5, 111.0 (Cq-Ar), 21.5 (CH3 of Ts). HRESIMS m/z found
278.0015 calcd. for C11H10ClNO2NaS (M+Na)+: 278.0013.
1,3-Dipolar cycloaddition of 2c with benzyl azide (Table 1, entry 3).
Following the general procedure and starting from 2c27d (110 mg, 0.259
mmol) in toluene for 3 h at 110 oC, pyrrole 4c (55 mg, 0.14 mmol, 54%) was
isolated after chromatographic purification (EtOAc:cyclohexane 1:10→1:5)
as a yellow oil. Unprotected pyrrole 6c was detected, but could not be
isolated. Compound 6c (64 mg, 0.21 mmol, 88%) was obtained separately
following the procedure reported for 6b after chromatographic purification
(EtOAc:cyclohexane 1:1) as a white solid.
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Data for 4c: IR (ῡ) 2922, 1752 (C=O), 1522, 1366, 1237, 816 cm-1. H-NMR (300 MHz, CDCl3) 
7.92-7.89 (m, 3H, H-Ar, H-2 or H-5), 7.32-7.29 (m, 2H, H-Ar), 7.25 (d, 1H, JH,H = 2.6, H-5 or H-2),
2.41 (s, 3H, CH3 of Ts), 1.59 (s, 9H, -C(CH3)3). 13C{1H}-NMR (75.4 MHz, CDCl3)  146.6 (C=O, Boc),
144.4, 138.2 (Cq-Ar), 129.7, 128.2 (C-Ar), 127.7 (Cq-Ar), 125.1, 122.5 (C-2, C-5), 97.6 (Cq-Ar), 86.8
(-C(CH3)3), 27.9 (-C(CH3)3), 21.7 (CH3 of Ts). HRESIMS m/z found 422.0024 calcd. for
C16H18BrNO4NaS (M+Na)+: 422.0032.
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Data for 6c: IR (ῡ) 3333 (NH), 2921, 1527, 1293, 1131, 809 cm-1. H-NMR (300 MHz, CD3OD) 
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5 or H-2), 2.38 (s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4 MHz, CD3OD)  145.2, 140.7 (Cq-Ar), 130.6,
128.5 (C-Ar), 125.9, 123.0 (C-2, C-5), 123.8, 94.8 (Cq-Ar), 21.5 (CH3 of Ts). HRESIMS m/z found
321.9506 calcd. for C11H10BrNO2NaS (M+Na)+: 321.9508.
1,3-Dipolar cycloaddition of 2d with benzyl azide (Table 1, entry 6).
Following the general procedure and starting from 2d27b (146 mg, 0.423
mmol) in toluene for 3 h at 110 oC, pyrrole 4d (81 mg, 0.25 mmol, 59%) was
isolated after chromatographic purification (EtOAc:cyclohexane 1:20→1:10)
as a white solid.
IR (ῡ) 2983, 1748, 1724 (C=O), 1507, 1373, 1253, 848 cm-1. 1H-NMR (300 MHz, CDCl3)  7.79 (d,
1H, JH,H = 2.6, H-2 or H-5), 7.25 (d, 1H, H-5 or H-2), 4.29 (q, 2H, JH,H = 7.1, -CH2CH3), 1.59 (s, 9H, -
C(CH3)3), 1.34 (t, 3H, -CH2CH3). 13C{1H}-NMR (75.4 MHz, CDCl3)  162.6 (C=O, COOEt), 147.2 (C=O,
Boc), 125.7, 121.5 (C-2, C-5), 117.8, 100.3 (C-3, C-4), 86.0 (-C(CH3)3), 60.5 (-CH2CH3), 27.9 (-
C(CH3)3), 14.4 (-CH2CH3). HRESIMS m/z found 340.0150 calcd. for C12H16BrNO4Na (M+Na)+:
340.0155.
1,3-Dipolar cycloaddition of 2d with benzyl azide (Table 1, entry 8).
Following the general procedure and starting from 2d27b (136 mg, 0.395 mmol) in MeOH for 7 h
at 65 oC, pyrrole 4d (43 mg, 0.14 mmol, 35%, white solid) and unprotected pyrrole 6d (31 mg,
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0.14 mmol, 35%, brown solid) were isolated after chromatographic purification
(EtOAc:cyclohexane 1:20→1:10→1:5→1:2).
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IR (ῡ) 3247 (NH), 2917, 1719, 1682 (C=O), 1512, 1320, 1158, 722 cm-1. 1H-NMR
(300 MHz, CDCl3)  9.07 (bs, 1H, NH), 7.41-7.40 (m, 1H, H-2 or H-5), 6.82 (ap. t,
1H, H-5 or H-2), 4.30 (q, 2H, JH,H = 7.1, -CH2CH3), 1.35 (t, 3H, -CH2CH3). 13C{1H}-
NMR (75.4 MHz, CDCl3)  163.9 (C=O), 124.9, 120.4 (C-2, C-5), 114.7, 97.4 (C-3, C-4), 60.2 (-
CH2CH3), 14.5 (-CH2CH3). HRESIMS m/z found 239.9627 calcd. for C7H8BrNO2Na (M+Na)+:
239.9631.
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1,3-Dipolar cycloaddition of 2f with benzyl azide (Table 1, entry 9).
Following the general procedure and starting from 2f (149 mg, 0.286 mmol) in toluene for 1 h
at 110 oC, pyrrole 4f (72 mg, 0.15 mmol, 53%, colorless oil) and triazoles 8f (20 mg, 0.042 mmol,
15%, yellow oil) and 9f (15 mg 0.030 mmol, 11%, yellow solid) were isolated after
chromatographic purification (EtOAc:cyclohexane 1:4). Unprotected pyrrole 6f was detected but
could not be isolated. Compound 6f (46 mg, 0.12 mmol, 92%) was obtained separately following
the procedure reported for 6b after chromatographic purification (EtOAc:cyclohexane 1:1) as a
white solid.
Data for 4f: IR (ῡ) 3391 (NH), 2979, 1757, 1704 (C=O), 1507, 1365, 1243,
841 cm-1. 1H-NMR (300 MHz, CDCl3)  7.93 (d, 2H, JH,H = 8.3, H-Ar), 7.89
(d, 1H, JH,H = 2.5, H-2 or H-5), 7.30-7.26 (m, 3H, H-Ar, H-5 or H-2), 5.14
(bs, 1H, NH), 3.26-3.20 (m, 2H, -CH2CH2NHBoc), 2.85 (t, 2H, JH,H = 6.2, -CH2CH2NHBoc), 2.40 (s,
3H, CH3 of Ts), 1.59 (s, 9H, -C(CH3)3), 1.42 (s, 9H, -C(CH3)3). 13C{1H}-NMR (75.4 MHz, CDCl3) 
155.9, 146.8 (C=O, Boc), 144.3, 138.6, (Cq-Ar), 130.0 (C-3), 129.6, 128.1 (C-Ar), 125.9, 125.8 (C-2,
C-5), 114.8 (C-4), 86.6, 79.4 (-C(CH3)3), 39.4 (-CH2CH2NHBoc), 36.7 (-CH2CH2NHBoc), 28.5, 27.9 (-
C(CH3)3), 21.7 (CH3 of Ts). HRESIMS m/z found 519.1592 calcd. for C23H32N2O6NaS2 (M+Na)+:
519.1594.
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Data for 8f: IR (ῡ) 3357 (NH), 2929, 1704 (C=O), 1454, 1248, 1161, 813
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cm-1. H-NMR (300 MHz, CDCl3)  7.43-7.38 (m, 2H, H-Ar), 7.33-7.25
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(m, 3H, H-Ar), 7.16-7.13 (m, 2H, H-Ar), 7.10-7.07 (m, 2H, H-Ar), 5.87
(s, 2H, CH2Ph), 5.04 (bs, 1H, NH), 3.46-3.40 (m, 2H, -CH2CH2NHBoc), 3.33-3.29 (m, 2H, -
CH2CH2NHBoc), 2.35 (s, 3H, CH3 of Ts), 1.44 (s, 9H, -C(CH3)3). 13C{1H}-NMR (75.4 MHz, CDCl3) 
155.9 (C=O), 146.4 (C-4), 145.8, 136.7, 134.3 (Cq-Ar), 132.3 (C-5), 129.9, 129.0, 128.6, 127.9,
127.4 (C-Ar), 79.6 (-C(CH3)3), 54.3 (CH2Ph), 40.3 (-CH2CH2NHBoc), 32.5 (-CH2CH2NHBoc), 28.5 (-
C(CH3)3), 21.8 (CH3 of Ts). HRESIMS m/z found 511.1438 calcd. for C23H28N4O4NaS2 (M+Na)+:
511.1444.
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Data for 9f: IR (ῡ) 3391 (NH), 2926, 1707 (C=O), 1497, 1250, 1145, 814
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cm-1. H-NMR (300 MHz, CDCl3)  8.00-7.96 (m, 2H, H-Ar), 7.35-7.31
(m, 5H, H-Ar), 7.30-7.25 (m, 2H, H-Ar), 5.62 (s, 2H, CH2Ph), 5.19 (bs,
1H, NH), 3.14 (q, 2H, JH,H = 5.7, -CH2CH2NHBoc), 2.80 (t, 2H, -CH2CH2NHBoc), 2.42 (s, 3H, CH3 of
Ts), 1.44 (s, 9H, -C(CH3)3). 13C{1H}-NMR (75.4 MHz, CDCl3)  155.9 (C=O), 151.2 (C-4), 145.5, 137.1,
134.0 (Cq-Ar), 131.4 (C-5), 130.0, 129.3, 129.1, 128.5, 128.1 (C-Ar), 79.7 (-C(CH3)3), 52.8 (CH2Ph),
39.6 (-CH2CH2NHBoc), 37.5 (-CH2CH2NHBoc), 28.5 (-C(CH3)3), 21.8 (CH3 of Ts). HRESIMS m/z
found 511.1438 calcd. for C23H28N4O4NaS2 (M+Na)+: 511.1444.
Data for 6f: IR (ῡ) 3334 (NH), 2976, 1683 (C=O), 1516, 1365, 1254, 813
cm-1. 1H-NMR (300 MHz, CD3OD)  7.87 (d, 2H, JH,H = 8.3, H-Ar), 7.50 (d,
1H, JH,H = 2.3, H-2 or H-5), 7.34-7.31 (m, 2H, H-Ar), 6.98 (d, 1H, H-5 or H-
2) 3.07 (t, 2H, JH,H = 6.7, -CH2CH2NHBoc), 2.62 (t, 2H, -CH2CH2NHBoc), 2.38 (s, 3H, CH3 of Ts), 1.42
(s, 9H, -C(CH3)3). 13C{1H}-NMR (75.4 MHz, CD3OD)  158.2 (C=O, Boc), 145.0, 141.2 (Cq-Ar), 130.4,
128.6 (C-Ar), 128.0, 126.5 (C-2, C-5), 126.7 (C-3), 111.7 (C-4), 80.1 (-C(CH3)3), 40.5 (-
CH2CH2NHBoc), 37.2 (-CH2CH2NHBoc), 28.8 (-C(CH3)3), 21.5 (CH3 of Ts). HRESIMS m/z found
419.1063 calcd. for C18H24N2O4NaS2 (M+Na)+: 419.1070.
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1,3-Dipolar cycloaddition of 2f with benzyl azide (Table 1, entry 11).
Following the general procedure and starting from 2f (150 mg, 0.287 mmol) in toluene for 58 h
at 50 oC, pyrrole 4f (129 mg, 0.260 mmol, 91%) was isolated after chromatographic purification
(EtOAc:cyclohexane 1:4) as a colorless oil.
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1,3-Dipolar cycloaddition of 2g with benzyl azide (Table 1, entry 12).
Following the general procedure and starting from 2g (149 mg,
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0.337 mmol) in toluene for 2 h at 110 C, pyrrole 4g (108 mg,
0.262 mmol, 78%) was isolated after chromatographic
purification (EtOAc:cyclohexane 1:5) as a white solid.
IR (ῡ) 3417 (NH), 2979, 1746, 1705 (C=O), 1509, 1370, 1255, 836 cm-1. 1H-NMR (300 MHz, DMSO-
d6)  7.77 (d, 1H, JH,H = 2.4, H-2 or H-5), 7.32 (d, 1H, H-5 or H-2), 7.04 (t, 1H, JH,H = 5.6, NH), 4.20
(q, 2H, JH,H = 7.1, -CH2CH3), 3.17-3.10 (m, 2H, -CH2CH2NHBoc), 2.88-2.83 (m, 2H, -CH2CH2NHBoc),
1.58 (s, 9H, -C(CH3)3), 1.38 (s, 9H, -C(CH3)3), 1.26 (t, 3H, -CH2CH3). 13C{1H}-NMR (75.4 MHz, DMSO-
d6)  162.4 (C=O, COOEt), 155.6, 146.9 (C=O, Boc), 125.7, 117.34 (C-2, C-5), 120.0 (C-3), 117.27
(C-4), 85.4, 77.8 (-C(CH3)3), 59.9 (-CH2CH3), 39.0 (-CH2CH2NHBoc), 31.5 (-CH2CH2NHBoc), 28.2,
27.4 (-C(CH3)3), 14.2 (-CH2CH3). HRESIMS m/z found 437.1713 calcd. for C19H30N2O6NaS (M+Na)+:
437.1717.
1,3-Dipolar cycloaddition of 3b with benzyl azide (Table 1, entry 15).
Following the general procedure and starting from 3b (157 mg, 0.554 mmol)
in toluene for 1 h at 110 oC, furan 5b (120 mg, 0.468 mmol, 85%, white solid)
and triazole 9b (24 mg, 0.069 mmol, 12%, pale yellow oil) were isolated after
chromatographic purification (EtOAc:cyclohexane 1:5).
Data for 5b: IR (ῡ) 3153, 1595, 1325, 1148, 817 cm-1. 1H-NMR (300 MHz, CDCl3)  8.03 (d, 1H, JH,H
= 1.9, H-2 or H-5), 7.92-7.88 (m, 2H, H-Ar), 7.43 (d, 1H, H-5 or H-2), 7.35-7.32 (m, 2H, H-Ar), 2.43
(s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4 MHz, CDCl3)  147.5, 141.8 (C-2, C-5), 145.1, 137.6 (Cq-Ar),
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130.0 (C-Ar), 128.3 (Cq-Ar), 128.2 (C-Ar), 113.7 (Cq-Ar), 21.8 (CH3 of Ts). HRESIMS m/z found
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278.9855 calcd. for C11H9ClO3NaS (M+Na)+: 278.9853.
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IR (ῡ) 3032, 1595, 1335, 1166, 813 cm-1. H-NMR (300 MHz, CDCl3)  7.98-7.94
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(m, 2H, H-Ar), 7.37-7.31 (m, 5H, H-Ar), 7.30-7.26 (m, 2H, H-Ar), 5.49 (s, 2H,
CH2Ph), 2.42 (s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4 MHz, CDCl3)  145.5 (Cq-Ar),
143.8 (C-4 or C-5), 137.2, 132.5 (Cq-Ar), 130.1, 129.29, 129.27, 128.3 (C-Ar), 127.4 (C-5 or C-4),
52.8 (CH2Ph), 21.8 (CH3 of Ts). HRESIMS m/z found 370.0385 calcd. for C16H14ClN3O2NaS (M+Na)+:
370.0387.
1,3-Dipolar cycloaddition of 3c with benzyl azide (Table 1, entry 16).
Following the general procedure and starting from 3c27d (119 mg, 0.364
mmol) in toluene for 1 h at 110 oC, furan 5c (86 mg, 0.29 mmol, 80%, white
solid) and triazole 9c (14 mg, 0.035 mmol, 10%, pale yellow oil) were isolated
after chromatographic purification (EtOAc:cyclohexane 1:5→1:2).
Data for 5c: IR (ῡ) 3127, 1594, 1323, 1148, 870 cm-1. 1H-NMR (300 MHz, CDCl3)  8.07-8.06 (m,
1H, H-2 or H-5), 7.93-7.91 (m, 2H, H-Ar), 7.45-7.44 (m, 1H, H-5 or H-2), 7.35-7.32 (m, 2H, H-Ar),
2.44 (s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4 MHz, CDCl3)  148.0, 144.0 (C-2, C-5), 145.1, 137.5 (Cq-
Ar), 129.9, (C-Ar), 129.4 (Cq-Ar), 128.4 (C-Ar), 97.7 (Cq-Ar), 21.8 (CH3 of Ts). HRESIMS m/z found
322.9347 calcd. for C11H9BrO3NaS (M+Na)+: 322.9348.
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IR (ῡ) 2923, 1595, 1338, 1157, 815 cm-1. H-NMR (300 MHz, CDCl3)  7.99-7.95
(m, 2H, H-Ar), 7.37-7.30 (m, 5H, H-Ar), 7.29-7.26 (m, 2H, H-Ar), 5.54 (s, 2H,
CH2Ph), 2.42 (s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4 MHz, CDCl3)  146.7 (C-4),
145.5, 137.2 (Cq-Ar), 132.7 (Cq-Ar), 130.1, 129.3, 129.2, 128.3, 128.26 (C-Ar), 113.5 (C-5), 53.6
(CH2Ph), 21.8 (CH3 of Ts). HRESIMS m/z found 413.9879 calcd. for C16H14BrN3O2NaS (M+Na)+:
413.9882.
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1,3-Dipolar cycloaddition of 3d with benzyl azide (Table 1, entry 17).
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colorless oil) and triazoles 7 (61 mg, 0.38 mmol, 66%, white solid), 8d (11 mg,
0.036 mmol, 6%, yellow oil) and 9d (43 mg, 0.14 mmol, 24%, white solid)
were isolated after chromatographic purification (EtOAc:cyclohexane
1:20→1:10→1:5→1:1→EtOAc).
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Data for 5d: IR (ῡ) 2982, 1729, 1715 (C=O), 1566, 1309, 1037, 875 cm-1. 1H-NMR (300 MHz, CDCl3)
 7.97 (d, 1H, J2,5 = 1.8, H-2), 7.46 (d, 1H, H-5), 4.31 (q, 1H, JH,H = 7.1, -CH2CH3), 1.34 (t, 3H, -
CH2CH3). 13C{1H}-NMR (75.4 MHz, CDCl3)  161.6 (C=O), 149.0 (C-2), 143.1 (C-5), 118.6 (C-4), 99.8
(C-3), 60.8 (-CH2CH3), 14.3 (-CH2CH3). HRESIMS m/z found 218.9648 calcd. for C7H8BrO3 (M+H)+:
218.9651.
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Data for 7: H-NMR (300 MHz, CDCl3)  7.62 (s, 1H, H-Ar), 7.41 (bs, 1H, H-Ar), 7.31-
7.25 (m, 3H, H-Ar), 7.19-7.16 (m, 2H, H-Ar), 5.48 (s, 2H, CH2Ph). Its spectroscopic data
are in accordance with those described in the bibliography.32
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Data for 8d: IR (ῡ) 2922, 1722 (C=O), 1512, 1328, 1274, 1102, 839 cm-1. H-
NMR (300 MHz, CDCl3)  7.37-7.26 (m, 5H, H-Ar), 5.91 (s, 2H, CH2Ph), 4.37 (q,
2H, JH,H = 7.1, -CH2CH3), 1.37 (t, 3H, -CH2CH3). 13C{1H}-NMR (75.4 MHz, CDCl3)
 157.7 (C=O), 134.6 (Cq-Ar), 131.1 (C-4), 129.0, 128.8, 128.1 (C-Ar), 126.1 (C-5), 62.4 (-CH2CH3),
55.0 (CH2Ph), 14.1 (-CH2CH3). HRESIMS m/z found 310.0184 calcd. for C12H13BrN3O2 (M+H)+:
310.0186.
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Data for 9d: IR (ῡ) 2921, 1731 (C=O), 1505, 1343, 1278, 1197, 844 cm-1. H-
NMR (300 MHz, CDCl3)  7.35-7.25 (m, 5H, H-Ar), 5.60 (s, 2H, CH2Ph), 4.42 (q,
2H, JH,H = 7.1, -CH2CH3), 1.40 (t, 3H, -CH2CH3). 13C{1H}-NMR (75.4 MHz, CDCl3)
 159.9 (C=O), 138.0 (C-4), 133.3 (Cq-Ar), 129.1, 128.9, 128.0 (C-Ar), 116.2 (C-5), 61.6 (-CH2CH3),
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53.2 (CH2Ph), 14.3 (-CH2CH3). HRESIMS m/z found 310.0184 calcd. for C12H13BrN3O2 (M+H)+:
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Following the general procedure and starting from 3e (151 mg, 0.403 mmol)
in toluene for 1 h at 110 oC, furan 5e (113 mg, 0.326 mmol, 81%, pale yellow
solid) and triazole 9e (14 mg, 0.033 mmol, 8%, pale yellow oil) were isolated
after chromatographic purification (EtOAc:cyclohexane 1:5→1:2).
Data for 5e: IR (ῡ) 2922, 1592, 1313, 1139, 810 cm-1. 1H-NMR (300 MHz, CDCl3)  8.08 (d, 1H, JH,H
= 1.8, H-2 or H-5), 7.94-7.90 (m, 2H, H-Ar), 7.43 (d, 1H, H-5 or H-2), 7.34-7.31 (m, 2H, H-Ar), 2.42
(s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4 MHz, CDCl3)  148.8, 148.1 (C-2, C-5), 144.9, 137.4 (Cq-Ar),
131.0 (C-4), 129.8, 128.5 (C-Ar), 62.1 (C-3), 21.8 (CH3 of Ts). HRESIMS m/z found 370.9204 calcd.
for C11H9IO3NaS (M+Na)+: 370.9209.
IR (ῡ) 2921, 1595, 1329, 1152, 813 cm-1. 1H-NMR (300 MHz, CDCl3)  7.98 (d, 2H,
JH,H = 8.3, H-Ar), 7.35-7.33 (m, 5H, H-Ar), 7.28-7.26 (m, 2H, H-Ar), 5.59 (s, 2H,
CH2Ph), 2.42 (s, 3H, CH3 of Ts). 13C{1H}-NMR (75.4 MHz, CDCl3)  151.2 (C-4),
145.4, 137.2, 133.1 (Cq-Ar), 130.1, 129.2, 129.1, 128.4, 128.2 (C-Ar), 81.8 (C-4), 55.0 (CH2Ph),
21.8 (CH3 of Ts). HRESIMS m/z found 461.9740 calcd. for C16H14IN3O2NaS (M+Na)+: 461.9744.
1,3-Dipolar cycloaddition of 3f with benzyl azide (Table 1, entry 20).
Following the general procedure and starting from 3f (151 mg, 0.355
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mmol) in toluene for 1 h at 110 C, furan 5f (127 mg, 0.320 mmol,
90%) was isolated after chromatographic purification
(EtOAc:cyclohexane 1:3) as a yellow oil.
IR (ῡ) 3386 (NH), 2977, 1700 (C=O), 1504, 1319, 1148, 872 cm-1. 1H-NMR (300 MHz, CDCl3)  8.05
(d, 1H, JH,H = 1.7, H-2 or H-5), 7.93 (d, 1H, JH,H = 8.3, H-Ar), 7.50 (ap. s, 1H, H-5 or H-2), 7.32 (d,
2H, H-Ar), 5.05 (bs, 1H, NH), 3.24 (q, 2H, JH,H = 6.0, -CH2CH2NHBoc), 2.85 (t, 2H, -CH2CH2NHBoc),
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2.42 (s, 3H, CH3 of Ts), 1.43 (s, 9H, -C(CH3)3). 13C{1H}-NMR (75.4 MHz, CDCl3)  155.9 (C=O, Boc),
148.4, 147.7 (C-2, C-5), 144.9, 137.9, 131.1 (Cq-Ar), 129.8, 128.2 (C-Ar), 114.4 (Cq-Ar), 79.6 (-
C(CH3)3), 39.4 (-CH2CH2NHBoc), 36.1 (-CH2CH2NHBoc), 28.5 (-C(CH3)3), 21.8 (CH3 of Ts). HRESIMS
m/z found 420.0906 calcd. for C18H23NO5NaS2 (M+Na)+: 420.0910.
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1,3-Dipolar cycloaddition of 3g with benzyl azide (Table 1, entry 21).
Following the general procedure and starting from 3g (150 mg,
0.440 mmol) in toluene for 1 h at 110 oC, furan 5g (128 mg, 0.405
mmol, 92%) was isolated after chromatographic purification
(EtOAc:cyclohexane 1:5) as a colorless oil.
IR (ῡ) 3379 (NH), 2983, 1687 (C=O), 1567, 1322, 1154, 880 cm-1. 1H-NMR (300 MHz, CDCl3)  8.00
(d, 1H, JH,H = 1.7, H-2 or H-5), 7.43 (d, 1H, H-5 or H-2), 5.09 (bs, 1H, NH), 4.29 (q, 1H, JH,H = 7.1, -
CH2CH3), 3.30 (bs, 2H, -CH2CH2NHBoc), 2.92 (t, 2H, JH,H = 6.5, -CH2CH2NHBoc), 1.41 (s, 9H, -
C(CH3)3), 1.33 (t, 3H, -CH2CH3). 13C{1H}-NMR (75.4 MHz, CDCl3)  162.6 (C=O, COOEt), 155.9 (C=O,
Boc), 149.6, 143.3 (C-2, C-5), 119.4, 117.4 (C-3, C-4), 79.6 (-C(CH3)3), 60.7 (-CH2CH3), 39.3 (-
CH2CH2NHBoc), 34.3 (-CH2CH2NHBoc), 28.5 (-C(CH3)3), 14.4 (-CH2CH3). HRESIMS m/z found
338.1029 calcd. for C14H21NO5NaS (M+Na)+: 338.1033.
Huisgen cycloaddition between 1e and benzyl azide: synthesis of triazoles 8e and 9e. To a
solution of 1e (50 mg, 0.16 mmol) in toluene (0.4 mL), a solution of benzyl azide (32 mg, 0.24
o
mmol) in toluene (0.3 mL) was added and the reaction mixture was stirred at 110 C for 1 h.
Then, the solvent was evaporated and the resulting residue was purified by chromatography
column on silica gel (EtOAc:cyclohexane 1:5→1:2) to give regioisomeric triazoles 8e (39 mg,
0.090 mmol) and 9e (35 mg, 0.079 mmol) as yellow oils in quantitative yield.
Data for 8e: IR (ῡ) 2921, 1593, 1334, 1141, 814 cm-1. 1H-NMR (300 MHz, CDCl3)  7.40-7.27 (m,
5H, H-Ar), 7.20-7.16 (m, 2H, H-Ar), 7.11-7.08 (m, 2H, H-Ar), 6.01 (s, 2H, -CH2Ph), 2.35 (s, 3H, CH3
of Ts). 13C{1H}-NMR (75.4 MHz, CDCl3)  146.1 (Cq-Ar), 137.6 (C-5), 136.2 (Cq-Ar), 134.2 (Cq-Ar),
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129.9, 129.1, 128.7, 128.0 (C-Ar), 94.8 (C-4), 55.0 (-CH2Ph), 21.8 (CH3 of Ts). HRESIMS m/z found
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461.9743 calcd. for C16H14IN3O2NaS (M+Na)+: 461.9744.
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Supporting information.
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/...
1
Example of the determination of the Path A/Path B ratio by H-NMR analysis of the
cycloaddition crude mixture.
Example of the determination of the percentage of N-Boc deprotection in β-substituted
pyrroles.
1H- and 13C-NMR spectra for new compounds.
1H-NMR spectra for known compounds.
Acknowledgements
This work was supported by the Ministerio de Economía y Competitividad of Spain (CTQ2016-
77270-R) and the Consejería de Economía y Conocimiento-Junta de Andalucía (FQM-345). E. Gil
de Montes thanks the Ministerio de Educación, Cultura y Deporte for a FPU fellowship. M.
Martínez-Bailén thanks the Junta de Andalucía-UE (Fondo Social Europeo-Iniciativa de Empleo
Juvenil) for a contract (EJ3-61). We also thank CITIUS-University of Seville (MS and NMR
services).
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β-Substituted pyrroles are often used as synthetic intermediates in the preparation of other complex
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