Expeditious synthesis of bicyclic pyrrolidine/pyrrolizidine/thiazolidine grafted macrocycles through intramolecular 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1016/j.tetlet.2013.09.064

Stereoselective synthesis of bicyclic pyrrolidine and pyrrolizidine grafted macrocycles has been accomplished through intramolecular 1,3-dipolar cycloaddition (1,3-DC) reaction. Alkenyl aldehydes 4a-b derived from salicylaldehyde have been reacted with se

Full text of DOI:10.1016/j.tetlet.2013.09.064

Tetrahedron Letters 54 (2013) 6450–6454
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Expeditious synthesis of bicyclic pyrrolidine/pyrrolizidine/
thiazolidine grafted macrocycles through intramolecular 1,3-dipolar
cycloaddition of azomethine ylides
⇑
S. Purushothaman, R. Prasanna, R. Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2013
Revised 13 September 2013
Accepted 14 September 2013
Available online 23 September 2013
Stereoselective synthesis of bicyclic pyrrolidine and pyrrolizidine grafted macrocycles has been accom-
plished through intramolecular 1,3-dipolar cycloaddition (1,3-DC) reaction. Alkenyl aldehydes 4a–b
derived from salicylaldehyde have been reacted with secondary aminoacids to generate azomethine
ylides which in turn were trapped intramolecularly by suitably placed dipolarophiles to give the corre-
sponding macrocycle in moderate yield. The structures were assigned by 2D NMR spectra and the regio-
and stereochemical outcome of the cycloadducts was established by a single crystal X-ray analysis of one
of the products.
Keywords:
Macrocycles
Cycloaddition
Pyrrolidine
Ó 2013 Elsevier Ltd. All rights reserved.
Intramolecular
Regioselective
Over the past few decades, macrocyclic compounds have been
extensively studied for their varied application in the field of
biology, material science, and supramolecular chemistry.1 Due to
their conformational bias and flexible nature, these molecules are
considered to be efficient molecular ligands for biological targets.2
Particularly, small macrocyclic rings with heterocyclic motifs are
found to be excellent molecular ligands because they are known
to interact with distinct protein molecules. Hence, macrocyclic
compounds have potential application in drug development and
discovery. In addition, macrocyclic compounds with large cavities
with appropriate functional groups have a tendency to recognize
metal ions. They act as fluorescent sensors for chiral molecules
and complex with small molecules in host–guest chemistry.3,4
There are numerous macrocyclic compounds known in the
literature with potential biological activity.5–7
Although many methods have been reported in the literature, a
short and efficient synthesis of heterocycle-grafted macrocycles
remains a challenge for synthetic organic chemists. The existing
methods require high dilute reaction conditions and long reaction
time. Nevertheless, 1,3-DC reaction8,9 of azomethine ylide is a
simple and efficient strategy for the stereo- and regioselective
construction of complex heterocyclic architectures having nitrogen
in a five-membered unit. They often constitute the core structure
of numerous alkaloids and pharmacologically important
compounds.10
As part of our ongoing research for the synthesis of complex and
novel heterocycle grafted macrocycles by cycloaddition methodol-
ogy,11 herein we report for the first time a one-pot intramolecular
1,3-dipolar cycloaddition of azomethine ylide for the construction
of pyrrolidine and pyrrolizidine grafted macrocycles starting from
salicylaldehyde (Scheme 1).
The monobromo alkene 3a–b can be easily obtained from
salicylaldehyde via aldol/Wittig reaction followed by controlled
O-alkylation (Scheme 2) in good yield.
The monobromo alkene 3a–b thus prepared was subjected to
O-alkylation with another mole of salicylaldehyde to give the
required alkenyl aldehyde 4a–b (Scheme 3). The structures of the
alkenyl aldehydes 4a–b were confirmed on the basis of spectro-
scopic data. The aldehydic proton resonated at d 10.49 as a singlet.
The geometry of the olefinic double bond was found to be E as evi-
denced by 1H NMR spectrum where the olefinic protons of 4b ap-
peared as doublets at d 7.25 and d 6.52 (J = 15.9 Hz).
With the available alkenyl aldehyde (4a–b), the cycloaddition
reactions were carried out with the azomethine ylide generated
by decarboxylative condensation with secondary amino acid
sarcosine (Scheme 4).12 The alkenyl aldehyde 4a was refluxed with
sarcosine 5a in toluene for 4 h under Dean–Stark reaction
condition. The azomethine ylide generated by decarboxylative
condensation underwent neat regioselective intramolecular
cycloaddition to yield novel macrocyclic grafted pyrrolidine 6a in
⇑
Corresponding author. Tel.: +91 44 22202811.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.064

S. Purushothaman et al. / Tetrahedron Letters 54 (2013) 6450–6454
6451
1,3-DC reaction
Wittig or
Me
O
Aldol reaction
N
COR
O
O
Hc
O
Ha
R
CHO
OH
H
Hb
ROC
O
Br
O
O
-alkylaton
O
Controlled -alkylation
O
Pyrrolidine grafted
Macrocycle (6a-b)
Salicylaldehyde
(1)
Alkenyl aldehyde
(4a-b)
Monobromo alkene
(3a-b)
Scheme 1. Synthetic plan for pyrrolidine grafted macrocycles 6a–b.
R
O
R
p-Cl-acetophenone,
aq.NaOH, rt-heat, 2h
EtOH,80%
O
OH
K2CO3 / DMF
rt, 4-6h
CHO
OH
Br
Br
OR
O
Br
Salicylaldehyde
Alkenyl alcohol
(2)
Ph3P-CHCO2Et
1,4-dibromobutane
Monobromo alkene
(1)
(3a-b)
80-85 % Yield
Reflux,
Et2O, 2h, 60 %
R= Br-p-C6H4- or -OEt
Scheme 2. Synthesis of monobromo alkene 3a–b.
O
R
Table 1
O
O
CHO
OH
Effect of solvent on the yield of the reaction
R
H
Solvent
Temperature
Time (h)
6b
Yielda (%)
6b
1
O
O
Br
6a
6a
K2CO3 / DMF
O
rt, 4-6h, 78-82%
4a:R= p-Br-C6H4-
Benzene
Toluene
Reflux
Reflux
Reflux
Reflux
110 °C
90 °C
6.5
4.2
8.0
7.0
3.5
8.0
45
62
55
Trace
—
42
72
51
Trace
—
Monobromo alkene
(3a-b)
Alkenyl aldehyde
(4a-b)
4b:R= OEt
Acetonitrile
Methanol#
DMF*
12.0
24.0
24.0
12.0
24.0
24.0
Scheme 3. Synthesis of alkenyl aldehyde 4a–b.
1,4-Dioxane*
—
—
a
#
*
Isolated yield.
Starting material recovered.
Reaction ended up with complex mixture.
moderate yield. In order to improve the yield of the reaction, we
have studied the solvent effects on the cycloaddition reaction for
the synthesis of 6a–b. It was observed that the reaction proceeded
more efficiently in toluene than benzene or other solvents
(Table 1).
The structure of the cycloadduct 6a was established by spectro-
scopic data. The 1H NMR spectrum of 6a exhibited a singlet at d
2.16 corresponding to the N-methyl group. The N-methylene pro-
tons resonated as two triplets at d 2.30 and d 3.58 (J = 8.7 Hz)
and the O-methylene protons exhibited as a multiplet in the range
of d 3.79–4.21. The benzylic Ha proton resonated as a multiplet in
the region of d 3.93–4.00, which clearly proved the regiochemistry
of the cycloaddition reaction. If the other possible regioisomer R2
(7a) had formed, then the benzylic Ha proton would have shown
a doublet of doublet instead of multiplet. The benzoyl proton
(Hb) appeared as a doublet of doublet at d 5.08 (J = 3.6, 7.2 Hz). A
doublet at d 4.72 (J = 7.2 Hz) was observed for one of the benzylic
(Hc) protons. The coupling constant of Hb and Hc protons clearly
suggested a cis fusion at the ring junction. The presence of O-meth-
ylene groups was confirmed by two signals at 68.8 and 69.3 ppm in
the 13C NMR spectrum of 6a. The carbonyl carbon exhibited a peak
at 202.3 ppm.
The H, H–COSY spectrum of 6a showed that N-methylene pro-
ton at d 2.30 has contour with the hydrogen at d 3.58. Furthermore,
these N-methylene protons have H, H-COSY relationship with the
Ha hydrogen at d 3.93–4.00. The Hb proton at d 5.08 has a contour
with Ha proton at d 3.93–4.00 as well as Hc protons at d 4.72.
This unambiguously further confirmed the observed regiochemist-
ry of the cycloaddition. The N-methylene carbon of 6a at
O
H
N
COR
Me
Me
H
N
N
O
Me
5a
OH
Hb
ROC
Me
Me
N
N
Hc
O
COR O
Ha
COR
H
O
O
O
Hb
Ha Hc
ROC
O
O
O
O
O
PATH A
PATH B
toluene, N2 atm
Dean-Stark, 3-4 h,
62-69%
toluene, N2 atm
Dean-Stark
Bicyclic Pyrrolidine
grafted macrocycle
(6a-b)
Fused Pyrrolidine
grafted macrocycle
(7a-b)
4a:R= -Br-C H -
p
6
4
4b:R= OEt
Regio isomer 2 (R2)
Regio isomer 1 (R1)
Scheme 4. Synthesis of pyrrolidine grafted macrocycles 6a–b.

6452
S. Purushothaman et al. / Tetrahedron Letters 54 (2013) 6450–6454
Ha-Hc
2.30 & 3.58
No NOESY
(J = 8.7 Hz, NCH2)
2.16 (s) & 39.6 ppm
Hb-Hc
64.5 ppm
H
Me
N
Strong NOESY
H
Me
N
3.93-4.00 (m, Ha)
4.72 (d, J = 9.5 Hz, Hc)
Hc
Ha
Hc
44.2 ppm
52.2 ppm
Ha
O
O
H
Hb
O
Hb
O
O
5.08(dd, J = 3.6, 7.2 Hz, H )
O
b
Br
Br
68.7ppm
HMBC NOESY
Figure 1. Key HMBC, 2D NOESY, and 1H & 13C signals.
58.52 ppm has a HSQC relationship with protons at d 2.30 & 3.58,
The methine carbon of 6a at 44.2, 68.7 and 52.2 ppm has a
C, H–COSY relationship with protons at d 3.93–4.00 (Ha), 5.08
(Hb), and 4.72 (Hc).
The doublet at d 4.72 (J = 7.2 Hz, Hc) and multiplet d 3.94 (Ha)
have an equal and strong gradient HMBC contour with the benzoyl
carbonyl carbons at 202.3 ppm which again confirmed the
observed regioselectivity and d values of the Ha, Hb, and Hc
protons. For the other possible regioisomer R2 the above HMBC
contour may not be equally strong for both Ha and Hc (Scheme 4).
The key HMBC, 2D NOESY, and chemical shifts are shown in
Figure 1.
Scheme 5 explains the formation of sterically more favorable fa-
cial selective exo adduct through TS1 not endo adduct. Even though
understating the regioselectivity of 1,3-DC reaction is a more diffi-
cult phenomenon, several theoretical studies explained the regi-
oselectivity based on unequal magnitudes of the terminal
coefficients of the frontier molecular orbital.13 Thus, the regio-
chemical outcome of the cycloadduct should depend mainly on
the maximum overlap between HOMO and LUMO of the reacting
species.
using B3LYP/6-31G⁄ level of theory using GAUSSIAN 09 program
package.14
As a logical extension of our methodology, we next investigated
the feasibility of synthesizing pyrrolizidine grafted macrocycles.
Thus, the alkenyl aldehydes 4a–b were subjected to [3+2]
cycloaddition with cyclic secondary amino acids, namely L-proline
and thiazolidine-4-carboxylic acid to yield the pyrrolizidine/
thiazolidine grafted macrocycles 8a–d in moderate yield
(Scheme 6).15 The results are summarized in Table 2.
The structures of the cycloadducts were established by spectro-
scopic data. The 1H NMR spectrum of the cycloadduct 8a exhibited
a multiplet in the range of d 1.86–1.92 for the pyrrolizidine ring
methylene protons. The benzylic proton Hb resonated as a doublet
of doublet at d 5.24 (J = 4.8, 9.0 Hz). The coupling constants of Hb
clearly proved the regio- and stereochemistry of the cycloaddition
reaction.
The presence of O-methylene groups was confirmed by the two
signals at 68.0 and 69.5 ppm in the 13C NMR and DEPT 135 spec-
trum of 8a. The carbonyl carbon exhibited a peak at 198.4 ppm.
Similar types of results were obtained for 8b–d in spectroscopic
studies.
Quantum chemical tools are useful to provide the structure and
energetic details of the reactions. Energetically the product R1 is
8.7 kcal/mol lower in energy than R2, this may be associated with
large steric hindrance in fused pyrrolidine structure (R2). This ex-
plains the formation of observed product but the knowledge of
particular path of the reaction is not clear (Scheme 4). To explain
the pathway, we have calculated the charges on the carbons of
the intermediate (Fig. 2). The calculation showed that the positive
charge is located on the benzylic carbon (Fig. 2; blue in color),
which explains that the reaction goes through path A to give the
expected products. All the DFT calculations have been carried out
Finally, the stereochemical outcome of the cycloaddition
reaction was confirmed by a single crystal X-ray analysis of the
cycloadduct 8c (Fig. 3).16
-0.04 a.u
Me
N
H2C
Me
Hc
Ha
H
N
O
0.14 a.u
Path A
Hb
ROC
O
O
Favored
O
COR
Bicyclic Pyrrolidine
Me
Intermediate (TS 1)
grafted macrocycle (R1)
R
N
H
H
Figure 2. The proposed intermediate in the 1,3 DC reaction. The Mulliken charges
were calculated at B3LYP/6-31G⁄ level of theory.
O
N
Me
H
exo attack for
regioisomer 1
ROC
O
O
O
O
Bicyclic Pyrrolidine
grafted macrocycle (R1)
X
TS 1
R
H
O
R
X
Hd
Ha
N
CO2H
5b-c
O
O
ROC
Me
Hc
O
N
N
H
O
H
N
Me
Hb
ROC
exo attack for
regioisomer 2
H
O
H
O
toluene,N2 atm
Dean-Stark, 4-6 h,
64-68 %
O
O
O
O
8a: R = p-Br-C6H4- ; X=-CH2-
8b: R = p-Br-C6H4-; X= -S-
8c: R = -OEt ; X=-CH2-
8d: R = - OEt; X= -S-
4a-b
8a-d
Fused Pyrrolidine
TS 2
grafted macrocycle (R2)
Scheme 5. Regioselectivity.
Scheme 6. Synthesis of pyrrolizidine/pyrorolothiazole grafted macrocycles 8a–d.

S. Purushothaman et al. / Tetrahedron Letters 54 (2013) 6450–6454
6453
Table 2
Synthesis of pyrrolidine grafted macrocycle via intramolecular 1,3-DC reaction
Acknowledgments
No
Structure
Time (h)
Yielda,b (%)
Purityc (%)
The author S.P. thanks DST, New Delhi for fellowship. The
authors wish to thank Professor D. Velmurugan and T. Srinivasan
for single crystal X-ray data. S.P. and R.P. thank CSIR, New Delhi
for the award of SRF. R.R. thanks DST for financial support and
UGC for BSR faculty fellowship.
Me
N
Hc
Ha
O
6a
4.2
62
90
Hb
O
O
Br
References and notes
Me
1. (a) Amabilino, D. B.; Stoddart, J. F. Chem. Rev. 1995, 95, 2725–2828; (b)
Hamilton, D. G.; Montalti, M.; Prodi, L.; Fontani, M.; Zanello, P.; Sanders, J. K. M.
Chem. Eur. J. 2000, 6, 608–617; (c) Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart,
J. F. Angew. Chem., Int. Ed. 2000, 39, 3349–3391; (d) Collier, C. P.; Mattersteig,
G.; Wong, E. W.; Luo, Y.; Beverley, K.; Sampaio, J.; Raymo, F. M.; Stoddart, J. F.;
Heath, J. R. Science 2000, 289, 1172–1175.
N
Hc
Ha
O
6b
8a
3.5
4.5
69
65
88
91
Hb
O
O
O
Me
2. (a) Schreiber, S. L. Science 1964, 2000, 287; (b) Berg, T. Angew. Chem., Int. Ed.
2003, 42, 2462–2481.
H
Had
N
3. (a) Lodeiro, C.; Capelo, J. L.; Mejuto, J. C.; Oliveira, E.; Santos, H. M.; Pedras, B.;
Núñez, C. Chem. Soc. Rev. 2010, 39, 2948–2976; (b) Camiolo, S.; Gale, P. A.;
Hursthouse, M. B.; Light, M. E. Org. Biomol. Chem. 2003, 1, 741–744.
4. (a) Núñez, C.; Aldrey, A.; García, V.; Bastida, R.; Macías, A.; Lodeiro, C. Inorg.
Chim. Acta 2012, 381, 85–94; (b) Bazzicalupi, C.; Bencini, A.; Matera, I.;
Puccioni, S.; Valtancoli, B. Inorg. Chim. Acta 2012, 381, 162–169.
Hc
O
O
Hb
O
Br
5. (a) Nagarajan, R. J. Antibiot. 1993, 46, 1181–1195; (b) Evans, D. A.; Watson, P. S.
Tetrahedron Lett. 1996, 37, 3251–3254.
6. (a) Corvalin, P. Antimicrob. Agents Chemother. 1990, 34, 2291–2296; (b) Imai, H.;
Suzuki, K.; Morioka, M.; Numasaki, Y.; Kadota, S.; Nagai, K.; Sato, T.; Iwanami,
M.; Saito, T. J. Antibiot. 1987, 40, 1475–1482.
7. (a) Smith, A. B., III; Basu, K.; Bosanac, T. J. Am. Chem. Soc. 2007, 129, 14872–
14874; (b) Frost, J. R.; Pearson, C. M.; Snaddon, T. N.; Booth, R. A.; Ley, S. V.
Angew. Chem., Int. Ed. 2012, 51, 9366–9371; (c) Smith, A. B., III; Rano, T. A.;
Chida, N.; Sulikowski, G. A.; Wood, J. L. J. Am. Chem. Soc. 1992, 114, 8008–8022.
8. (a) Prasanna, R.; Purushothaman, S.; Raghunathan, R. Tetrahedron Lett. 2010, 51,
4538–4542; (b) Purushothaman, S.; Prasanna, R.; Niranjana, P.; Raghunathan,
R.; Nagaraj, S.; Rengasamy, R. Bioorg. Med. Chem. 2010, 20, 7288–7291; (c)
Waldmann, H. Synlett 1995, 133–141.
S
H
N
Had
Hc
O
8b
8c
8d
5.5
4.2
5.5
66
68
64
94
94
91
O
O
Hb
Br
H
Had
N
Hc
O
O
Hb
O
9. (a) Prasanna, R.; Purushothaman, S.; Suresh, M.; Raghunathan, R. Tetrahedron
Lett. 2011, 52, 792–797; (b) Poornachandran, M.; Raghunathan, R. Tetrahedron:
Asymmetry 2008, 19, 2177–2183.
10. (a) Liddell, J. R. Nat. Prod. Rep. 1996, 13, 187–193; (b) Nyerges, M.; Gajdics, L.;
Szollosy, A.; Toke, L. Synlett 1999, 111–113.
O
Me
S
H
Had
N
11. (a) Purushothaman, S.; Raghunathan, R. Tetrahedron Lett. 2009, 50, 6848–6850;
(b) Kathiravan, S.; Raghunathan, R. Synlett 2009, 1126–1130.
Hc
O
O
Hb
12. General procedure for the synthesis of macrocylic pyrrolidinesA/pyrrolizidine/
thiazolidine 6a–b and 8a–d: To a solution of alkenyl aldehyde 4a–b (0.6 mmol)
and sarcosine 5a/L-proline 5b/thiazolidine-4-carboxylic acid 5c (0.6 mmol)
was refluxed in dry toluene under N2 atmosphere for 3–6 h at 110 °C using
Dean–Stark apparatus. After the completion of reaction as indicated by TLC,
toluene was evaporated under reduced pressure. The crude product was
washed with water and extracted with dichloromethane (4 Â 20 mL). The
combined organic layers were dried (MgSO4), filtered, and concentrated in
vacuum. The crude product was purified by column chromatography using
hexane:ETOAC (8:2) mixture as eluent.
O
O
Me
Isolated products were characterized by 1H NMR, 13C NMR, mass, and X-ray
diffraction analysis of cycloadduct 8c.
a
b
Yields refer to pure isolated products after purification by silica gel column
chromatography.
c
Purity by HPLC using C18 column of the isolated adducts (CH3CN:H2O = 90:10
Pyrrolidine grafted macrocycle 6a: Yield: 62% (196 mg); white solid; mp 228–
230 °C. 1H NMR (300 MHz, CDCl3): d 1.96–2.06 (m, 2H); 2.09–2.12 (m, 2H);
2.16 (s, 3H); 2.30 (t, J = 8.7 Hz, 1H); 2.38–2.44 (m, 1H); 3.58 (t, J = 8.7 Hz, 1H);
3.79–3.85 (m, 1H); 3.93–4.00 (m, 1H); 4.06–4.10 (m, 1H); 4.18–4.21 (m, 1H);
4.71 (d, J = 7.2 Hz, 1H); 5.08 (dd, J = 3.6, 7.2 Hz, 1H); 6.47 (d, J = 8.1 Hz, 1H);
6.65 (t, J = 7.2 Hz, 1H); 6.80 (t, J = 7.5 Hz, 1H); 6.86–6.92 (m, 2H); 7.02 (d,
J = 7.5 Hz, 1H); 7.10–7.17 (m 4H); 7.24–7.26 (m, 2H). 13C NMR (125 MHz,
CDCl3): 22.6, 25.3, 40.6, 44.2, 52.2, 64.5, 68.7, 68.8, 69.3, 111.8, 113.6, 120.4,
121.4, 126.6, 127.6, 127.8, 128.1, 129.4, 130.2, 130.6, 131.8, 132.4, 137.4, 156.8,
157.2, 202.3 ppm. ESI Mass m/z: 506.14 (M++1); Anal. Calcd for C28H28BrNO3:
C, 66.41; H, 5.57; N, 2.77. Found: C, 66.49; H, 5.67; N, 2.62.
and 1 mL/min).
Pyrrolidine grafted macrocycle 6b: Yield: 72% (230 mg); white solid; mp 220–
222 °C. 1H NMR (300 MHz, CDCl3): d 0.67 (t, J = 7.2 Hz, 3H); 1.88–1.89 (m, 4H);
2.16 (s, 3H); 2.38 (t, J = 8.7 Hz, 1H); 2.37–2.41 (m, 1H); 2.59–2.61 (m, 1H);
3.21–3.29 (m, 1H); 3.51 (t, J = 8.7 Hz, 1H); 3.84–4.05(m, 2H); 3.97–4.04 (m,
2H); 4.06–4.16 (m, 2H); 6.78–6.83 (m, 2H); 6.86–6.92 (m, 2H); 7.10–7.15 (m,
3H); 7.32 (d, J = 7.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): 14.3, 24.6, 26.7, 33.5,
37.1, 41.1, 52.2, 56.4, 63.4, 67.6, 67.8, 110.5, 113.3, 116.9, 117.8, 124.6, 125.3,
126.4, 127.4, 128.9, 129.9, 131.1, 133.1, 136.2, 154.8, 157.3, 167.8 ppm. ESI
Mass m/z: 396.12 (M++1); Anal. Calcd for C24H29NO4: C, 72.89; H, 7.39; N, 3.54.
Found: C, 72.93; H, 7.45; N, 3.45.
13. (a) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646–10647; (b) Houk,
K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem. Soc. 1973, 95, 7301–7315.
14. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven,
T.; Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.;
Figure 3. ORTEP diagram of 8c.

6454
S. Purushothaman et al. / Tetrahedron Letters 54 (2013) 6450–6454
Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
129.5, 130.3, 130.7,133.5, 134.6, 134.5, 155.9, 156.1, 198.4.ESI Mass m/z:
532.25 (M++1); Anal. Calcd for C30H30BrNO3: C, 67.67; H, 5.68; N, 2.63. Found:
C, 67.57; H, 5.75; N, 2.72.
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. S.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. GAUSSIAN 09, Revision A.02;
GAUSSIAN, Inc.: Wallingford, CT, 2009.
Pyrrolothiazole grafted macrocycle 8d: Yield: 64% (227 mg); white solid; mp
255–257 °C. 1H NMR (300 MHz, CDCl3: d 1.22 (t, J = 7.5 Hz, 3H); 1.69–1.84
(m, 2H); 1.92–2.05 (m, 2H); 2.20–2.25 (m, 2H); 2.36–2.35 (m, 2H); 3.24–3.36
(m, 1H); 3.30 (d, J = 11.1 Hz, 1H); 3.28–3.86 (m, 1H); 4.11–4.23 (m, 3H);
4.23–4.26 (m, 2H); 4.38–4.40 (m, 1H); 5.36 (dd, J = 8.7, 1.5 Hz, 1H); 6.56–6.90
(m, 2H); 6.93–6.92 (m, 2H); 7.02–7.24 (m, 3H); 7.22–7.32 (m, 3H); 7.33–7.36
(m, 2H). 13C NMR (75 MHz, CDCl3): 14.5, 22.4, 22.6, 26.2, 34.5, 33.9, 54.5, 55.9,
57.8, 69.5, 71.4, 73.9, 108.9, 121.4, 122.2, 123.3, 123.7, 124.5, 127.3, 127.4,
131.2, 133.4, 154.5, 155.1, 165.4 ppm. ESI Mass m/z: 440.27 (M++1); Anal.
Calcd for C25H29NO4S: C, 68.31; H, 5.65; N, 3.19. Found: C, 68.40; H, 5.55; N,
3.27.
15. Pyrrolizidine grafted macrocycle 8a: Yield: 65% (208 mg); white solid; mp 254–
256 °C. 1H NM (300 MHz, CDCl3: d 1.86–1.92 (m, 3H); 1.94–1.97(m, 2H); 2.08–
2.13 (m, 3H); 2.29–2.48 (m, 2H); 3.15–3.16 (m, 1H); 3.51–3.55(m, 1H); 3.77–
3.78 (m, 1H); 3.92 (t, J = 9.9 Hz, 1H); 4.03–4.13 (m, 2H); 4.18–4.21 (m, 1H);
5.24 (dd, J = 9.0, 4.8 Hz, 1H); 6.64–6.70 (m, 2H); 6.81 (t, J = 7.2 Hz, 1H); 6.93(d,
J = 8.1 Hz, 1H); 6.99–7.04 (m, 2H); 7.16–7.18 (m, 2H); 7.19–7.22 (m, 2H); 7.26–
7.29 (m, 2H). 13C NMR (75 MHz, CDCl3): 24.4, 26.2, 27.4, 28.6, 46.4, 51.6, 61.1,
68.0, 69.5, 72.3, 75.5, 110.9, 114.3, 119.7, 120.6, 124.4, 126.2, 128.3, 128.7,
16. Narayanan, S.; Srinivasan, T.; Purushothaman, S.; Raghunathan, R.;
Velmurugana, D. Acta Cryst. 2013, E69, o25.