General synthetic methods for the preparation of pinwheel receptors

Article abstract of DOI:10.1016/S0040-4020(01)01075-4

The synthesis of bis-trityl diynes, used as cooperative fluorescent chemosensors, is described. The most convenient sequence for the preparation of the sensor framework was found to be intolerant of most functionality. Therefore, an unfunctionalized frame

Full text of DOI:10.1016/S0040-4020(01)01075-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 10233±10240
General synthetic methods for the preparation
of pinwheel receptors
Joseph Raker and Timothy E. Glassp
Department of Chemistry, The Pennsylvania State University, 152 Davey Laboratory, University Park, PA 16802, USA
Received 18 September 2001; revised 30 October 2001; accepted 1 November 2001
AbstractÐThe synthesis of bis-trityl diynes, used as cooperative ¯uorescent chemosensors, is described. The most convenient sequence for
the preparation of the sensor framework was found to be intolerant of most functionality. Therefore, an unfunctionalized framework is
constructed and recognition elements are selectively installed via electrophilic substitution on an electronically differentiated key inter-
mediate. A divergent synthesis of a general class of chemical sensors emerges. This synthetic method is highlighted by its simplicity and
modularity allowing for the introduction of various recognition elements and ¯uorophores. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
(Fluor) which is read spectroscopically. It is anticipated
that this framework will serve as a convenient platform
for sensing various analytes, as any binding event should
register a ¯uorescent response regardless of the recognition
element employed or the analyte targeted. In order for such
a sensor platform to be truly general, a divergent synthetic
procedure is required. Ideally, a common synthetic inter-
mediate would be used to append any recognition element
and any ¯uorophore. Herein is described our approach to
such a divergent synthetic strategy.
Fluorescent chemosensors have become an increasingly
valuable tool for real time detection of analytes in their
native environment.1 Generally speaking, a chemosensor
is a receptor with a ¯uorescent tag that modulates its
¯uorescent properties upon binding of an analyte to the
receptor. Many schemes have been developed for con-
verting a binding event into a ¯uorescent signal.2 We have
recently reported a novel chemical sensor framework in
which cooperativity is used to enhance the af®nity of the
sensor for its analyte.3 In this sensor, the ¯uorescent groups
are part of the recognition element and ¯uorescence quench-
ing correlates with metal ion binding. With a view toward
generating a general sensor platform, we have developed a
second-generation cooperative chemical sensor (compound
1, Fig. 1) in which the recognition elements are separate
from the ¯uorescent read-out.4 In this sensor design, binding
of the analyte (A) between the pairs of recognition elements
(R) causes an interaction between a pair of ¯uorophores
2. Results and discussion
Compound 1 is a bis-trityl butadiyne in which each trityl
group is substituted with two recognition elements (R) and
one ¯uorophore (Fluor). Prior to this work, only the parent
unsubstituted bistritylbutadiyne was known.5 Initially, this
class of compounds appeared to be readily accessible via
Glaser coupling6 of the corresponding monotritylacetylene.
However, the most convenient preparation of trityl acetyl-
ene compounds entails both strong acid and strong base
conditions, limiting the functionality that can be incorpo-
rated into the recognition elements or ¯uorophores.7 This
Figure 1. Two site cooperative chemosensor, with an integrated ¯uorescent
reporter. RˆRecogntion element, Fluorˆ¯uorescent Group, Aˆanalyte.
Keywords: molecular recognition; ¯uorescent chemosensors; receptors;
trityl; triphenylmethyl.
p
Corresponding author. Fax: 11-814-863-8403;
e-mail: teg@chem.psu.edu
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01075-4

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J. Raker, T. E. Glass / Tetrahedron 57 (2001) 10233±10240
Scheme 1.
limitation is particularly constraining in light of the sensi-
tivity of many common ¯uorophores. The synthetic pro-
cedure for compound 1 must address these limitations
with a view toward incorporating various recognition
elements as well as ¯uorophores.
Scheme 2.
As a proof of concept, compound 2 was chosen as the initial
synthetic target. Ethylene diamine groups were designed as
recognition elements for metal ions2a and naphthyl sulfona-
nilides were designed as ¯uorescent groups. The naphthyl
sulfonanilide was chosen because aryl sulfonanilides are
stable to strong acid and strong base conditions. Moreover,
aryl sulfonanilides can be deprotected under reductive
conditions and the aniline nitrogen which results can then
be used as a handle to attach different ¯uorophores.
converted to trityl acetylene 9 in moderate yield. Free
radical bromination of compound 9 gave dibromide 10.
Displacement of the bromides of 10 with N,N,N0-trimethyl
ethylene diamine yielded the binding group appended trityl
acetylene 11 in good overall yield. We were disappointed to
®nd that Glaser coupling of 11 yielded only trace amounts
of compound 12, though a variety of conditions were
tested.10,11 The low yield of the Glaser coupling was attri-
buted to oxidation of the amine recognition elements.
The trityl acetylene from which compound 2 would be
derived, could be easily obtained from the corresponding
trityl alcohol, however, the conditions are typically harsh:
chlorination under acidic conditions followed by addition of
acetylene Grignard at elevated temperature.8 Unfortunately,
variously substituted trityl alcohols 5a±c (Scheme 1)
prepared en route to compound 2 failed to provide the corre-
sponding trityl acetylenes 6a±c due to the instability of
the functional groups to the reaction conditions. Neither
amines, dioxolanes, nor protected benzylic alcohols
provided clean products despite attempts at using more
mild conditions.
Recognizing the low functional group tolerance of the
synthetic procedure, we explored alternative methods of
introducing the required functionality at a later stage. We
designed intermediate 13 with four anisole groups and a pair
of protected aniline groups. The advantage of this
compound is that the recognition elements could be
installed via electrophilic chemistry on the anisole rings,
and the ¯uorophores attached at the aniline nitrogens. The
C3 position of the anisole groups is most reactive toward
electrophiles since the tri¯uoroacetanilide deactivates the
remaining aromatic groups. Furthermore, the butadiyne
spacer should be unreactive toward electrophiles, as it is
suf®ciently sterically encumbered. Importantly, the anisole
groups should be compatible with conditions for formation
of the trityl acetylene. This methodology was particularly
attractive because the wide range of electrophilic aromatic
Recognizing that benzylic functionality was not tolerated in
this system, simple methyl substituents were then used,
anticipating that free radical halogenation followed by
alkylation would produce the desired recognition elements.
We reasoned that the methyl group of the N-methyl sul-
fonanilide might participate in a radical substitution
reaction, therefore, the ¯uorophore was changed to a simple
naphthyl (Scheme 2). Thus, ethyl-3-bromobenzoate was
coupled to the zincate of 2-bromonaphthalene to form
naphthyl ester 7,9 which was converted to trityl alcohol 8.
Now, the relatively unfunctionalized alcohol 8 was

J. Raker, T. E. Glass / Tetrahedron 57 (2001) 10233±10240
10235
of compound 15 gave the tetraanisole intermediate 16 in
good yield. Compound 16 was deprotected under mild
reductive conditions.13 The resulting anilines were repro-
tected as the tri¯uoroacetanilides to produce compound 13
in good overall yield (Scheme 4).
With the key intermediate 13 in hand, electrophilic formyl-
ation produced the tetraaldehyde 17 with no sign of any
other regiochemical isomers. These results validated our
supposition that the methoxy substituents would be
amenable to the trityl acetylene preparation procedure and
would serve as a handle to install the necessary functional
groups after construction of the framework. Reductive
amination yielded compound 18 following deprotection of
the tri¯uoroacetanilides. Any number of amine reactive
¯uorescent groups could be appended at this stage.14 For
example, pyrene acetic acid was coupled to compound 18
in order to yield compound 19 which acts as a sensor for
metal ions. Thus, compound 13 represents a key inter-
mediate in the synthesis of bis-tritylbutadiynes as the
anisole groups allow for the selective installation of binding
groups via electrophilic aromatic substitution, and the
suitably protected aniline groups can be unmasked, and
condensed with a variety of ¯uorescent groups.
Scheme 3.
substitution chemistry would lend itself to a general strategy
for incorporation of recognition elements.
Thus, intermediate 13 was synthesized as shown in Scheme
3. Trityl alcohol 14 was prepared from ester 312 and was
smoothly converted to trityl acetylene 15. The ability of the
methoxy groups to stabilize the carbocation intermediate
greatly facilitated the chlorination/Grignard addition
sequence resulting in higher overall yield. Glaser coupling
Having successfully prepared a metal ion sensor, we wanted
to show that this strategy would be generally applicable to
other sensors with different recognition elements and ¯uoro-
phores. For example, compound 20 was designed to bind
dicarboxylates in a cooperative fashion similar to sensor 19.
This compound differs from 19 in that it has a larger phenyl-
diyne spacer, guanidinium recognition elements and anthra-
cene ¯uorophores. Yet, this sensor could be constructed
from an electronically differentiated intermediate using
the same synthetic strategy as described earlier.
The synthesis of compound 20 is shown in Scheme 5. In this
case, the naphthalene sulfonanilide of compound 15 was
exchanged with a tri¯uoroacetanilide to give compound
21. This trityl acetylene was coupled to 1,4-diiodobenzene
under Sonogashira conditions15 to give the complete skele-
ton 22 in excellent yield. Nitration of 22 with ammonium
nitrate and tri¯uoroacetic anhydride gave the desired tetra-
nitro compound with no trace of undesired regioisomers.
Reduction of the nitro groups with Sn(II) gave tetraamine
23. The guanidine recognition elements were then installed
by reaction with bis-BOC thiourea in the presence of
mercury (II) chloride.16 Removal of the tri¯uoroacetanilides
gave the protected tetra guanidine 24. Addition of the
anthracenesulfonyl chloride appended the ¯uorophores
Scheme 4.

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J. Raker, T. E. Glass / Tetrahedron 57 (2001) 10233±10240
Scheme 5.
and deprotection of the BOC groups gave the ®nal sensor
20.17 Thus, the generality of this strategy was demonstrated.
(1.0 mL, 8.5 mmol), trimethylethylene diamine (2.2 mL,
17.1 mmol), acetic acid (10 mL), and abs. ethanol (90 mL)
Ê
was stirred at room temperature, over 4 A mol sieves for
6.5 h. The reaction was cooled to 08C, and NaBH4 (1.61 g,
42.7 mmol) was added slowly. The reaction was allowed to
stir at room temperature for 10 h. The reaction was poured
slowly over ice water, and then made basic with 10 M
NaOH. The aqueous layer was extracted with 3£25 mL
CHCl3, and dried over MgSO4. The solvent was removed
in vacuo, and the resulting residue was puri®ed via ¯ash
chromatography (ammoniated MeOH/CHCl3, 10:90). The
title compound 4a was afforded as a yellow oil (2.25 g,
8.3 mmol, 97% yield); 1H NMR (360 MHz) d 2.21 (s,
6H), 2.22 (s, 3H), 2.40±2.50 (m, 4H), 3.47 (s, 2H), 7.16
(t, Jˆ7.7 Hz, 1H), 7.24 (d, Jˆ7.7 Hz, 1H), 7.36 (d, Jˆ
7.8 Hz, 1H), 7.49 (s, 1H); 13C NMR (75 MHz) d 42.9,
46.2, 55.6, 57.8, 62.7, 122.8, 127.9, 130.1, 130.4, 132.2,
141.9; IR (neat) 3058, 2941, 2766, 1594, 1569, 1464,
1360, 1263, 1125, 1068, 1030, 690, 670 cm21; HRMS
calcd for C12H20NBr (M1H1): 271.0810, found: 271.0812.
3. Conclusions
In conclusion, we have developed the synthesis of a novel
class of ¯uorescent, cooperative chemical sensors based on
two differing bis-trityl diyne core structures. The frame-
works are prepared by oxidative or palladium catalyzed
coupling of a trityl acetylene, which is derived from the
corresponding trityl alcohol. Although the sequence to
bis-trityl diynes is ef®cient, it is intolerant of virtually any
functionality. Therefore, we developed two key inter-
mediates, 13 and 22, which are differentiated electronically
such that recognition elements could be installed via
electrophilic substitution chemistry and ¯uorophores could
be appended to an amine functionality. This synthetic
method is divergent in that different types of sensors can
in principle be derived from a common intermediate. The
preparation of various sensors based on this methodology is
currently underway in our laboratory.
4.1.2. Compound 5a. n-BuLi (890 mL, 2.22 mmol, 2.5 M in
hexanes) was added to a stirred solution of THF (25 mL)
and compound 4a (617 mg, 2.27 mmol) at 2788C. The
reaction mixture was allowed to stir for 20 min, followed
by addition of compound 3 (210 mg, 0.57 mmol) at 2788C.
The reaction mixture was allowed to warm to 08C, and
quenched with NaHCO3. The aqueous layer was extracted
with CH2Cl2 (3£10 mL). The organic layer was dried over
MgSO4, and the solvent removed in vacuo. Flash chroma-
tography (ammoniated MeOH/CHCl3, 10:90) afforded the
title compound 5a as a yellow oil (360 mg, 0.51 mmol, 89%
4. Experimental
4.1. General
All reactions were carried out in dried glassware under
argon atmosphere unless otherwise noted. Tetrahydrofuran
(THF) and benzene were distilled from sodium benzo-
phenone ketyl under argon immediately before use. Meth-
ylene chloride (CH2Cl2) and triethyl amine (Et3N) were
distilled from CaH2 under argon immediately before use.
Flash chromatography18 was performed with 32±63 mm
silica gel. All melting points are uncorrected. NMR spectra
were recorded on a Bruker WP-200, AC-200, DPX-300,
AMX-360, DRX-400, or AMX-500 in CDCl3 using TMS
as a reference unless otherwise noted.
1
yield); H NMR (360 MHz) d 2.14 (s, 12H), 2.16 (s, 6H),
2.36±2.42 (m, 8H), 3.14 (s, 3H), 3.44 (s, 4H), 6.88 (d, Jˆ
7.7 Hz, 2H), 7.00 (s, 1H), 7.08±7.27 (m, 9H), 7.37 (dd, Jˆ
8.6, 1.8 Hz, 1H), 7.55±7.65 (m, 2H), 7.72 (d, Jˆ8.7 Hz,
1H), 7.84±7.87 (m, 2H), 8.14 (s, 1H); 13C NMR (90 MHz)
d 38.6, 42.9, 46.2, 55.4, 57.7, 63.1, 81.9, 123.6, 126.1,
126.3, 127.0, 127.5, 127.8, 128.0, 128.3, 128.5, 128.7,
128.8, 129.1, 129.2, 129.4, 129.7, 132.4, 134.0, 135.2,
139.1, 141.5, 146.9; IR (neat) 3056, 2945, 2777, 1600,
4.1.1. Compound 4a. A solution of 3-bromobenzaldehyde

J. Raker, T. E. Glass / Tetrahedron 57 (2001) 10233±10240
10237
1463, 1349, 1266, 1165, 1029, 909, 787, 733, 653 cm21
;
removed in vacuo, and the resulting residue was puri®ed
via ¯ash chromatography (EtOAc/hex, 1:99) to afford the
title compound 7 as a white crystalline solid (2.06 g,
HRMS calcd for C42H54N5O3S (M1Na1): 708.3947,
found: 708.3962.
1
7.42 mmol, 71% yield), mp 101±1038C; H NMR (200
4.1.3. Compound 5b. n-BuLi (510 mL, 1.28 mmol, 2.5 M
in hexanes) was added to a stirred solution of THF (15 mL)
and 2-(3-bromophenyl)-1,3-dioxolane (0.20 mL, 1.35 mmol)
at 2788C. The reaction mixture was allowed to stir for
20 min, followed by addition of compound 3 (200 mg,
0.54 mmol) at 2788C. The reaction mixture was allowed
to warm to 08C, and quenched with NH4Cl. The aqueous
layer was extracted with CH2Cl2 (3£10 mL). The organic
layer was dried over MgSO4, and the solvent removed in
vacuo. Flash chromatography (EtOAc/hex, 50:50) afforded
the title compound 5b as a white amorphous solid (314 mg,
0.50 mmol, 93% yield); 1H NMR (300 MHz) d 2.92 (s, 1H),
3.11 (s, 3H), 3.90±4.06 (m, 8H), 5.68 (s, 2H), 36.92 (s, 1H),
7.01 (d, Jˆ7.9 Hz, 2H), 7.13±7.25 (m, 5H), 7.33±7.38 (m,
5H), 7.53±7.64 (m, 2H), 7.71 (d, Jˆ8.7 Hz, 1H), 7.84 (t,
Jˆ7.2 Hz, 2H), 8.14 (s, 1H); 13C NMR (90 MHz) d 38.6,
65.7, 81.9, 104.0, 123.6, 125.9, 126.0, 126.3, 126.8, 127.4,
127.8, 128.3, 128.4, 128.9, 129.1, 129.3, 129.5, 129.7,
134.0, 135.2, 138.2, 141.7, 146.8, 147.9; IR (neat) 3475,
3058, 3017, 2974, 2889, 2251, 1589, 1503, 1483, 1438,
1348, 1166. 1074, 966, 908, 798, 652 cm21; HRMS calcd
for C36H32NO6S (M2OH): 606.1950, found: 606.1954.
MHz) d 1.44 (t, Jˆ7.1 Hz, 3H), 4.44 (q, Jˆ7.2 Hz, 2H),
7.49±7.60 (m, 3H), 7.77 (dd, Jˆ1.9, 8.6 Hz, 1H), 7.86±
7.97 (m, 4H), 8.06 (dt, Jˆ1.4, 7.7 Hz, 2H), 8.09 (d, Jˆ
1.0 Hz, 1H), 8.41 (t, Jˆ1.8 Hz, 1H); 13C NMR d 14.8,
61.5, 125.7, 126.4, 126.6, 126.9, 128.1, 128.7, 128.8,
128.9, 129.0, 129.3, 131.5, 132.1, 133.2, 134.0, 137.9,
141.7, 167.0; IR (neat) 3047, 2979, 1716, 1584, 1366,
1302, 1250, 1224, 1108, 813, 756 cm21; HRMS calcd for
C19H17O2 (M1H1): 277.1228, found: 277.1215.
4.1.6. Compound 8. n-BuLi (6.4 mL, 15.9 mmol, 2.5 M in
hexanes) was added to a stirred solution of THF (175 mL)
and 3-bromotoluene (2.15 mL, 17.7 mmol) at 2788C. The
reaction mixture was allowed to stir for 20 min, followed by
addition of compound 7 (979 mg, 3.54 mmol) at 2788C.
The reaction mixture was allowed to warm to 08C, and
quenched with NH4Cl. The aqueous layer was extracted
with CH2Cl2 (3£25 mL). The organic layer was dried over
MgSO4, and the solvent removed in vacuo. Flash chroma-
tography (EtOAc/hex, 5:95) afforded the title compound 8
as a white amorphous solid (1.28 g, 3.08 mmol, 87% yield);
1H NMR (360 MHz) d 2.33 (s, 6H), 2.86 (s, 1H), 7.05±7.12
(m, 4H), 7.18±7.25 (m, 5H), 7.41 (t, Jˆ7.6 Hz, 1H), 7.46 (d,
Jˆ4.3 Hz, 1H), 7.49 (t, Jˆ1.2 Hz, 1H), 7.62±7.70 (m, 2H),
7.75 (t, Jˆ1.8 Hz, 1H), 7.82±7.90 (m, 3H), 7.98 (d, Jˆ
1.6 Hz, 1H); 13C NMR (100 MHz) d 21.6, 82.1, 125.2,
125.6, 125.8, 125.9, 126.2, 126.21, 126.8, 127.1, 127.6,
127.8, 128.1, 128.14, 128.3, 128.31, 128.4, 132.5, 133.6,
137.6, 138.4, 140.6, 146.8, 147.6; IR (neat) 3456, 3055,
2920, 1601, 1486, 1443, 1320, 1140, 1017, 908, 792, 730,
4.1.4. Compound 5c. n-BuLi (460 mL, 1.15 mmol, 2.5 M in
hexanes) was added to a stirred solution of THF (10 mL)
and 3-(t-butyldiphenylsiloxymethyl)-bromobenzene19 (506
mg, 1.19 mmol) at 2788C. The reaction mixture was
allowed to stir for 20 min, followed by addition of
compound 3 (177 mg, 0.48 mmol) at 2788C. The reaction
mixture was allowed to warm to 08C, and quenched with
NH4Cl. The aqueous layer was extracted with CH2Cl2
(3£10 mL). The organic layer was dried over MgSO4, and
the solvent removed in vacuo. Flash chromatography
(EtOAc/hex, 30:70) afforded the title compound 5c as a
white amorphous solid (445 mg, 0.44 mmol, 91% yield);
1H NMR (200 MHz) d 1.01 (s, 18H), 2.54 (s, 1H), 3.11 (s,
3H), 4.69 (s, 4H), 6.99±7.02 (m, 3H), 7.12±7.24 (m, 7H),
7.26±7.40 (m, 15H), 7.49 (td, Jˆ7.3, 1.6 Hz, 1H), 7.55 (td,
Jˆ6.8, 1.3 Hz, 1H), 7.60±7.63 (m, 9H), 7.76 (d, Jˆ3.7 Hz,
1H), 7.78 (d, Jˆ3.3 Hz, 1H), 8.10 (s, 1H); 13C NMR d 19.7,
27.3, 38.6, 65.9, 82.1, 123.6, 125.5, 125.7, 126.6, 126.8,
127.5, 127.8, 128.1, 128.3, 128.4, 128.7, 129.1, 129.2,
129.5, 129.6, 130.1, 132.3, 133.8, 133.8, 133.9, 135.2,
136.0, 141.3, 141.7, 146.8, 148.3; IR (neat) 3499, 3070,
2930, 2857, 1600, 1484, 1427, 1349, 1165, 1112, 1074,
909, 823, 703 cm21; HRMS calcd for C64H65NO5SSi2Na
(M1Na1): 1038.4020, found: 1038.4046.
;
707 cm21 HRMS calcd for C31H26ONa (M1Na1):
437.1881, found: 437.1897.
4.1.7. Compound 9. A solution of compound 8 (931 mg,
2.24 mmol) and acetyl chloride (20 mL) was stirred at room
temperature for 3 h. The solvent was removed in vacuo, and
the resulting solid was dried under high vacuum for 1 h. The
solid was redissolved in benzene (25 mL) and ethynyl-
magnesium bromide (22.4 mL, 11.22 mmol, 0.5 M in
THF) was added. The reaction mixture was stirred at rt
for 48 h. The reaction was quenched with NH4Cl, and the
aqueous layer was extracted with CH2Cl2 (3£10 mL). The
organic layer was dried over MgSO4, and the solvent
removed in vacuo. Flash chromatography (ether/hex, 1:99)
afforded the title compound 9 (489 mg, 1.16 mmol, 52%), as
1
a viscous oil; H NMR (200 MHz) d 2.31 (s, 6H), 2.75 (s,
1H), 7.03±7.23 (m, 9H), 7.39 (t, Jˆ7.8 Hz, 1H), 7.44±7.49
(m, 2H), 7.59±7.68 (m, 2H), 7.84 (t, Jˆ1.7 Hz, 1H), 7.8±
7.88 (m, 3H), 8.02 (d, Jˆ0.86 Hz, 1H); 13C NMR (100
MHz) d 22.06, 55.9, 74.0, 90.4, 126.0, 126.2, 126.3,
126.7, 128.0, 128.2, 128.2, 128.6, 128.7, 128.7, 128.8,
130.2, 133.0, 134.0, 138.1, 141.1, 145.1, 146.0; IR (neat)
3288, 3054, 2919, 1600, 1485, 907, 857, 820, 786, 774, 725,
702, 650, 473 cm21; HRMS calcd for C33H26 (M1Na1):
437.1881, found: 437.1897.
4.1.5. Compound 7. n-BuLi (8.8 mL, 22.0 mmol, 2.5 M in
hex) was added to a stirred solution of 2-bromonaphthalene
(4.33 g, 20.9 mmol) and THF (225 mL) at 2788C. The reac-
tion was allowed to stir at 2788C for 15 min ZnCl2
(25.1 mL, 25.1 mmol, 1.0 M in diethyl ether) was added,
and the reaction was warmed to rt. To this solution,
Pd(PPh3)4 (2.43 g, 2.1 mmol) and ethyl-3-bromobenzoate
(1.67 mL, 10.5 mmol) was added, and the reaction was
stirred at 658C for 48 h. The reaction was quenched with
NH4Cl. The aqueous layer was extracted with CH2Cl2
(3£50 mL) and dried over MgSO4. The solvent was
4.1.8. Compound 10. Benzoyl peroxide (18 mg, 0.072
mmol) was added to a solution of N-bromosuccinimide
(710 mg, 3.99 mmol), compound 9 (766 mg, 1.81 mmol),

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J. Raker, T. E. Glass / Tetrahedron 57 (2001) 10233±10240
and CCl4 (20 mL) in a sealed tube. The reaction was stirred
at 908C for 24 h. N-bromosuccinimide (162 mg, 0.91 mmol)
and benzoyl peroxide (18 mg, 0.072 mmol) were added, and
the reaction was stirred at 908C for 8 h. The reaction was
cooled to rt, and ®ltered. The solvent was removed in vacuo
and the resulting residue was puri®ed via ¯ash chroma-
tography (EtOAc/hex, 2:98). The title compound 10 was
obtained as an impure solid and carried on without further
puri®cation.
afforded the title compound 21 as a white amorphous solid
(9.2 g, 20.4 mmol, 95% yield); 1H NMR (360 MHz) d 2.71
(s, 1H), 3.29 (s, 3H), 3.77 (s, 6H), 6.82 (dt, Jˆ2.7, 8.9 Hz,
4H), 7.13±7.15 (m, 6H), 7.33±7.35 (m, 2H); 13C NMR
(75 MHz) d 40.0, 54.4, 55.6, 74.0, 89.8, 113.9, 116.8 (q,
Jˆ288 Hz), 126.1, 128.5, 129.5, 130.0, 130.4, 136.8, 140.7,
148.0, 157.2 (q, Jˆ35.7 Hz), 159.0; IR (neat) 3291, 3062,
2935, 2837, 1698, 1605, 1506, 1300, 1116, 1035, 910,
704 cms21; HRMS calcd for C26H23NO3F3 (M1H1):
454.1630, found: 454.1630.
4.1.9. Compound 11. A solution of trimethylethylene
diamine (0.50 mL, 3.96 mmol), compound 10 (115 mg,
0.20 mmol), Et3N (0.2 mL), and DMF (1.8 mL) was stirred
at 908C for 3 h. The reaction was cooled to rt and the solvent
was removed in vacuo. The resulting residue was puri®ed
via ¯ash chromatography (Et3N/EtOAc, 50:50). The title
compound 11 was obtained as a yellow oil (66 mg,
4.1.11. Compound 22. Pd(PPh3)2Cl2 (526 mg, 0.750 mmol)
was added to a solution of compound 21 (6.80 g,
15.0 mmol), copper (I) iodide (286 mg, 1.50 mmol), and
diiodobenzene (2.47 g, 7.50 mmol) in THF (30 mL) and
diisopropylamine (30 mL, deoxygenated by sparging with
argon prior to use). The reaction was stirred at 608C for 14 h.
After cooling to room temperature, the solvent was removed
in vacuo. The resulting residue was dissolved in CH2Cl2
(50 mL), and washed with saturated NH4Cl (50 mL). The
aqueous layer was extracted with CH2Cl2 (3£50 mL), and
the collected organic layers were dried over MgSO4. After
removal of the solvent in vacuo, the residue was puri®ed via
¯ash chromatography (CH2Cl2), and the title compound 22
was isolated as light brown solid (6.95 g, 14.3 mmol, 94%
1
0.11 mmol, 72% yield (2-steps); H NMR (300 MHz) d
2.15 (s, 12H), 2.18 (s, 6H), 2.36±2.43 (m, 8H), 2.74 (s,
1H), 3.49 (s, 4H), 7.11±7.14 (m, 2H), 7.18±7.27 (m, 5H),
7.34 (s, 2H), 7.38 (t, Jˆ7.8 Hz, 1H), 7.44±7.48 (m, 2H),
7.60±7.64 (m, 2H), 7.71 (t, Jˆ1.7 Hz, 1H), 7.81±7.86 (m,
3H), 7.92 (s, 1H); 13C NMR (75 MHz) d 42.8, 46.0, 55.2,
55.9, 57.5, 63.1, 74.1, 90.2, 125.9, 126.2, 126.3, 126.4,
126.7, 128.0, 128.2, 128.3, 128.4, 128.5, 128.5, 128.6,
128.7, 128.8, 130.3, 133.0, 134.0, 138.4, 139.0, 141.1,
145.0, 145.9; IR (neat) 3297, 3054, 2942, 2813, 2769,
1
yield). Mp 234±2368C (decomp.); H NMR (400 MHz) d
3.30 (s, 6H), 3.80 (s, 12H), 6.80 (d, Jˆ8.9 Hz, 8H), 7.15±
7.20 (m, 12H), 7.35±7.38 (m, 4H), 7.43 (s, 4H); 13C NMR
(100 MHz) d 39.6, 54.6, 55.2, 84.8, 96.7, 113.5, 116.3 (q,
Jˆ288 Hz), 123.0, 125.6, 128.1, 129.1, 129.5, 129.9, 131.4,
136.7, 140.3, 147.9, 156.8 (q, Jˆ35.8 Hz), 158.5; IR (neat)
3037, 3002, 3000, 2934, 2837, 2254, 1694, 1603, 1505,
1300, 1199, 1115, 1035, 910, 833 cm21; HRMS calcd for
C58H47F6N2O6 (M1H1): 981.3338, found: 981.3342.
1810, 1599, 1484, 1464, 1029, 791, 729, 705 cm21
;
HRMS calcd for C43H51N4 (M1H1): 623.4114, found:
623.4125.
4.1.10. Compound 21. Compound 15 (12.5 g, 22.8 mmol)
and Mg turnings (55.4 g, 2.28 mol) were added to a stirred
solution of CH2Cl2 (1 L) and MeOH (1 L). The reaction was
cooled to 08C. After 10 min, the reaction began to re¯ux,
and continued until most of the Mg had dissolved. The
solution was stirred at 08C for 5 h. The solvent was removed
in vacuo, and the residue was brought up in 50% AcOH
(aq.), and extracted with CH2Cl2 (3£300 mL). The solvent
was removed in vacuo, and the residue was dissolved in
CH2Cl2 (500 mL) and washed with saturated NaHCO3.
The aqueous layer was extracted with CH2Cl2 (3£
100 mL), and the combined organics were dried over
MgSO4. After removal of the solvent in vacuo, the residue
was puri®ed via ¯ash chromatography (EtOAc/hex, 1:4),
and the free aniline was isolated as a white solid (7.7 g,
4.1.12. Compound 23. Ammonium nitrate (2.26 g, 28.2
mmol) was added to a stirred solution of CH2Cl2 (75 mL)
and compound 22 (6.93 g, 7.06 mmol) at ambient tempera-
ture. Tri¯uoroacetic anhydride (13.9 mL, 98.8 mmol) was
added to the reaction. The reaction was stirred at ambient
temperature for 2 h. The mixture was slowly poured over
saturated NaHCO3 (200 mL), and the aqueous layer was
extracted with CH2Cl2 (3£50 mL). The organic layer was
dried over MgSO4, and the solvent removed in vacuo. The
resulting residue was puri®ed via ¯ash chromatography
(Et2O/CH2Cl2, 1:19) and the tetranitro compound was
isolated as a yellow amorphous solid (6.33 g, 5.43 mmol,
1
21.5 mmol, 94% yield). Mp 121±1228C; H NMR (300
1
MHz) d 2.65 (s, 1H), 2.75 (s, 3H), 3.62 (s, 1H), 3.78 (s,
6H), 6.46±6.56 (m, 3H), 6.80 (dt, Jˆ2.7, 9.0 Hz, 4H), 7.10
(t, Jˆ8.3 Hz, 1H), 7.19 (dt, Jˆ2.7, 9.0 Hz, 4H); 13C NMR
(75 MHz) d 30.7, 54.1, 55.2, 72.7, 90.3, 110.3, 113.1, 113.9,
118.3, 128.7, 130.1, 137.4, 146.2, 149.0, 158.2; IR (neat)
3416, 3285, 3000, 2953, 2835, 1606, 1504, 1298, 1248,
1178, 1034, 910, 830 cm21; HRMS calcd for C24H24NO2
(M1H1): 358.1807, found: 358.1800.
77%); H NMR (400 MHz) d 3.35 (s, 6H), 4.00 (s, 12H),
7.15 (d, Jˆ9.0 Hz, 4H), 7.23 (s, 2H), 7.29 (d, Jˆ7.9 Hz,
2H), 7.37 (d, Jˆ8.1 Hz, 2H), 7.47±7.53 (m, 10H), 7.84 (d,
Jˆ2.3 Hz, 4H); 13C NMR (75 MHz) d 39.5, 54.0, 56.6,
86.6, 94.2, 113.6, 120.2 (q, Jˆ288.4 Hz), 122.4, 125.6,
126.7, 127.7, 129.0, 129.9, 131.6, 134.2, 135.6, 139.0,
140.8, 145.1, 152.2, 156.4 (q, Jˆ35.7 Hz). IR (neat) 3062,
2979, 2945, 2845, 1700, 1619, 1533, 1498, 1353, 1283,
1204, 1153, 1089, 1018, 898, 756, 706 cm21. HRMS for
M1H1 calcd for C58H43F6N6O14: 1161.2741, found:
1161.2739.
Tri¯uoroacetic anhydride (15.2 mL, 107.5 mmol) was
added to a stirred solution of THF (200 mL) and the
above aniline (7.7 g, 21.5 mmol) at 08C. The solution was
warmed to ambient temperature and quenched with satu-
rated NaHCO3 (200 mL). The aqueous layer was extracted
with CH2Cl2 (3£100 mL), and the collected organic layers
were dried over MgSO4. Removal of the solvent in vacuo
Tin chloride dihydrate (3.25 g, 12.7 mmol) was added to a
stirred solution of MeOH (6 mL), THF (6 mL), and the
above tetranitro compound (738 mg, 0.636 mmol). The
reaction was stirred at 708C for 3.5 h. The reaction was

J. Raker, T. E. Glass / Tetrahedron 57 (2001) 10233±10240
10239
cooled, and the solvent removed in vacuo. The resulting
residue was dissolved THF (10 mL), and poured over a
saturated solution of NaHCO3 (50 mL). The aqueous layer
was made basic (pH.10) with 10 M NaOH and extracted
with CH2Cl2 (3£10 mL). The organic layer was dried over
MgSO4, and the solvent removed in vacuo. The resulting
residue was puri®ed via ¯ash chromatography (THF/
CH2Cl2, 1:19) and the title compound 23 was isolated as a
128.3, 128.4, 128.6, 128.6, 129.1, 129.4, 130.1, 131.1,
131.7, 132.1, 132.8, 133.0, 137.1, 141.0, 146.0, 148.9,
152.9, 153.1, 163.6. IR (neat) 3258, 2979, 1798, 1724,
1639, 1407, 1340, 1232, 1135, 1058, 1028, 732 cm21
.
HRMS for M1H1 calcd for C126H140N14O24S2: 2297.9685,
found: 2297.9665.
Tri¯uoroacetic acid (1 mL) and CH2Cl2 (1 mL) were added
to a ¯ask containing the above sulfonanilide (9.6 mg,
0.00420 mmol). The reaction was stirred at ambient
temperature for 2.5 h. Removal of the solvent in vacuo
afforded the title compound 20 as a yellow amorphous
1
yellow amorphous solid (533 mg, 0.515 mmol, 81%); H
NMR (300 MHz) d 3.30 (s, 6H), 3.73 (s, 8H), 3.84 (s,
12H), 6.55 (dd, Jˆ2.3, 6.2 Hz, 4H), 6.67 (d, Jˆ2.2 Hz,
4H), 6.69 (d, Jˆ8.5 Hz, 4H), 7.11 (d, Jˆ7.5 Hz, 2H), 7.20
(s, 2H), 7.31±7.38 (m, 4H), 7.41 (s, 4H); 13C NMR
(75 MHz) d 39.6, 54.8, 55.4, 84.4, 97.2, 109.5, 115.9,
116.4 (q, Jˆ288. Hz), 119.0, 123.1, 125.4, 128.2, 128.8,
129.7, 131.4, 135.6, 137.3, 140.0, 146.3, 148.2, 156.8 (q,
Jˆ35.6 Hz). IR (neat) 3472, 3376, 3002, 2956, 2933, 2837,
2242, 1695, 1616, 1512, 1433, 1283, 1231, 1154, 1031, 910,
733 cm21. HRMS for M1H1 calcd for C58H51F6N6O6:
1041.3774, found: 1041.3773.
1
solid (8.2 mg, 0.00420 mmol, 100%); H NMR (500 MHz,
CD3OD) d 3.26 (s, 6H), 3.85 (s, 12H), 6.97 (d, Jˆ9.5 Hz,
4H), 7.03 (s, 4H), 7.17±7.20 (m, 10H), 7.27±7.32 (m, 6H),
7.33 (t, Jˆ7.9 Hz, 2H), 7.46±7.49 (m, 4H), 7.96 (d, Jˆ
8.8 Hz, 2H), 7.99±8.01 (m, 4H), 8.36 (s, 2H), 8.42 (s,
2H), 8.51 (s, 2H); 13C NMR (125 MHz, CD3OD) d 38.8,
56.0, 56.7, 87.3, 97.0, 113.4, 122.9, 123.9, 124.0, 126.7,
127.8, 127.9, 128.1, 128.4, 129.2, 129.5, 129.6, 129.8,
130.0, 130.2, 130.8, 130.9, 131.4, 131.7, 132.5, 133.3,
134.0, 134.3, 134.9, 138.8, 143.2, 146.9, 155.5, 158.6,
162.3 (q, Jˆ36 Hz). IR (KBr pellet) 3368, 3154, 1676,
1631, 1596, 1560, 1508, 1282, 1203, 1140, 832,
4.1.13. Compound 24. To a stirred solution of N,N0-bis-
(t-butoxycarbonyl)thiourea (684 mg, 2.52 mmol), com-
pound 23 (262 mg, 0.252 mmol), Et3N (0.5 mL), and
CH2Cl2 (4.5 mL) at 08C, was added HgCl2 (684 mg,
2.52 mmol). The reaction was allowed to warm over a
period of 1 h, then ®ltered through a pad of celite. The
solvent was removed in vacuo, and the resulting residue
was dissolved in CH2Cl2 (5 mL) and added to a sealed
tube with ammoniated MeOH (5 mL). The reaction was
allowed to stir at ambient temperature for 16 h. The reaction
was then ®ltered, and the solvent removed in vacuo. The
resulting residue was puri®ed via ¯ash chromatography
(Et2O/CH2Cl2, 1:49) to yield the title compound 24 as a
2
722 cm21. HRMS for M23H1±4CF3CO2 calcd for
C86H77N14O8S2: 1497.5490, found: 1497.5420.
Acknowledgements
This work was supported by the National Institutes of
Health (GM 59245, RR 10524). J.R. thanks the Pennsyl-
vania State University for a Dalalian graduate fellowship.
1
white amorphous solid (358 mg, 0.197 mmol, 78%); H
NMR (300 MHz) d 1.36 (s, 36H), 1.51 (s, 36H), 2.76 (s,
6H), 3.86 (s, 12H), 6.46 (dd, Jˆ1.3, 7.2 Hz, 2H), 6.79 (d,
Jˆ8.8 Hz, 8H), 7.14 (t, Jˆ8.2 Hz, 2H), 7.21 (dd, Jˆ2.4,
8.6 Hz, 4H), 7.44 (s, 4H), 8.16 (d, Jˆ2.4 Hz, 4H); 13C
NMR (75 MHz) d 28.1, 30.7, 55.3, 56.0, 78.8, 83.0, 85.6,
97.2, 109.8, 110.0, 114.2, 118.6, 123.4, 125.0, 125.3, 125.9,
128.7, 131.5, 138.0, 146.0, 148.8, 149.1, 152.9, 153.2,
163.3. IR (neat) 3406, 3376, 3260, 2978, 1724, 1639,
1494, 1408, 1341, 1136, 1058, 733 cm21. HRMS for M1
H1 calcd for C98H125N14O20: 1817.9194, found: 1817.9195.
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