Generation of 3- and 5-lithiothiophene-2-carboxylates via metal-halogen exchange and their addition reactions to chalcogenoxanthones

Article abstract of DOI:10.1021/jo062370x

Deprotonation and lithium-bromine exchange in 5- or 3-bromothiophene-2- carboxylic acids with t-BuLi form the corresponding dianion, which reacts highly regioselectively in the presence of 0.25 equiv of tetramethyl-1,2- ethylenediamine with 3,6-bis(dimethylamino) chalcogenoxanthones to give S- and Se-containing rhodamines. Quenching studies with D₂O indicate that an extra equivalent of t-BuLi is not necessary in these reactions. Deprotonation is faster than metal-halogen exchange with the bromothiophene-2-carboxylic acids using t-BuLi.

Full text of DOI:10.1021/jo062370x

CHART 1
Generation of 3- and
5-Lithiothiophene-2-carboxylates via
Metal-Halogen Exchange and Their Addition
Reactions to Chalcogenoxanthones
Michael K. Gannon, II and Michael R. Detty*
Department of Chemistry, UniVersity at Buffalo, The State
UniVersity of New York, 627 Natural Sciences Complex,
North Campus, Buffalo, New York 14260
appeared to be a direct route to rhodamine-related structures
with a 9-thienyl substituent bearing a carboxylic acid oxidation
state without masking/protecting the carboxy substituent. Di-
anions 5 and 6 are both known in the literature from acid-
base chemistrysnot from metal-halogen exchange. Thiophene-
2-carboxylic acid is deprotonated with lithium diisopropylamide
(LDA) in THF at -78 °C to give dianion 56 and with n-BuLi
in THF at -78 °C to give dianion 6.7
mdetty@buffalo.edu
ReceiVed NoVember 16, 2006
In this paper, we describe the preparation of chalcogenor-
hodamines 7-11 (Chart 1) using dianions 5 and 6 generated
from 5-bromothiophene-2-carboxylic acid (12) and 3-bro-
mothiophene-2-carboxylic acid (13), respectively, via metal-
halogen exchange with tert-butyllithium (t-BuLi). These studies
include our observations with respect to rates of lithium-
bromine exchange relative to rates of deprotonation of the
carboxylic acids and the relative rate of elimination of HBr from
the 2-bromo-2-methylpropane generated in the metal-halogen
exchange.
Deprotonation and lithium-bromine exchange in 5- or
3-bromothiophene-2-carboxylic acids with t-BuLi form the
corresponding dianion, which reacts highly regioselectively
in the presence of 0.25 equiv of tetramethyl-1,2-ethylene-
diamine with 3,6-bis(dimethylamino) chalcogenoxanthones
to give S- and Se-containing rhodamines. Quenching studies
with D2O indicate that an extra equivalent of t-BuLi is not
necessary in these reactions. Deprotonation is faster than
metal-halogen exchange with the bromothiophene-2-car-
boxylic acids using t-BuLi.
Synthesis of 9-(Heteroaryl)chalcogenorhodamines. Our
initial studies with dianions 5 and 6 generated by acid-base
chemistry6,7 suggested that either these dianions were not formed
regiospecifically or they were equilibrating under reaction
conditions. Metal-halogen exchange in 5-bromothiophene-2-
carboxylic acid (12) and 3-bromothiophene-2-carboxylic acid
(13) was examined as a means of generating dianions 5 and 6
regiospecifically. As described below, reactions with t-BuLi
gave better regioselectivity than reactions with s-BuLi.
We have recently described the synthesis of thio and seleno
analogues of tetramethylrosamine and initial studies of their
photophysical1 and biological properties.2-4 Currently, we are
developing synthetic routes to heavy-chalcogen analogues of
true rhodamines; i.e., derivatives bearing a carboxy substituent
in the 9-aryl group. Rhodamines with a thienyl group in the
9-position of the xanthylium core absorb at longer wavelengths
than 9-phenyl derivatives and the parent compounds in this series
were prepared by the addition of 2-lithiothiophene (1, Chart 1)
to the 2-S and 2-Se5 to give dyes 3 and 4 in excellent yield.2c,3
The addition of lithium 5-lithiothiophene-2-carboxylate (5) and
lithium 3-lithiothiophene-2-carboxylate (6) to the xanthones 2
Initial metal-halogen exchange reactions followed conditions
used for generating dianions from aromatic bromo carboxylic
acids.9,10 Bromo acid 12 was treated with 3.1 equiv of t-BuLi
at -78 °C in THF in the presence or absence of 1 equiv (relative
to t-BuLi) of N,N,N′,N′-tetramethylethylenediamine (TMEDA)
to generate dianion 5, which was then added to thioxanthone
2-S or selenoxanthone 2-Se at -78 °C. After 3 h, the desired
rhodamines 8 and 9 were isolated in low yields (<10%) and
little chalcogenoxanthone was recovered.
* To whom correspondence may be sent: Tel: (716)-645-6800x2200. Fax:
(716)-645-6963.
(1) Ohulchanskyy, T.; Donnelly, D. J.; Detty, M. R.; Prasad, P. N. J.
Dianion 5, generated from 12 and 2.1 equiv of t-BuLi at -78
°C in THF, showed little reactivity toward either 2-S or 2-Se
after 3 h at either 0 °C or -78 °C in the absence of TMEDA.
Phys. Chem. B 2004, 108, 8668.
(2) (a) Detty, M. R.; Prasad, P. N.; Donnelly, D. J.; Ohulchanskyy, T.;
Gibson, S. L.; Hilf, R. Bioorg. Med. Chem. 2004, 12, 2537. (b) Gibson, S.
L.; Holt, J. J.; Ye, M.; Donnelly, D. J.; Ohulchanskyy, T. Y.; You, Y.;
Detty, M. R. Biorg. Med. Chem. 2005, 13, 6394. (c) Wagner, S. J.;
Skripchenko, A.; Donnelly, D. J.; Ramaswamy, K.; Detty, M. R. Biorg.
Med. Chem. 2005, 13, 5927.
(3) Tombline, G.; Donnelly, D. J.; Holt, J. J.; You, Y.; Ye, M.; Gannon,
M. K.; Nygren, C. L.; Detty, M. R. Biochemistry 2006, 45, 8034.
(4) Holt, J. J.; Gannon, M. K.; Tombline, G.; McCarty, T. A.; Page, P.
M.; Bright, F. V.; Detty, M. R. Biorg. Med. Chem. 2006, 14, 8635.
(5) Del Valle, D. J.; Donnelly, D. J.; Holt, J. J.; Detty, M. R.
Organometallics 2005, 24, 3807.
(6) Knight, D. W.; Nott, A. P. J. Chem. Soc., Perkin Trans. 1 1983,
791.
(7) Carpenter, A. J.; Chadwick, D. J. Tetrahedron Lett. 1985, 26, 1777.
(8) (a) Parham, W. E.; Sayed, Y. A. J. Org. Chem. 1974, 39, 2051. (b)
Parham, W. E.; Sayed, Y. A. J. Org. Chem. 1974, 39, 2053.
(9) Mortier, J.; Moyroud, J.; Bennetau, B.; Cain, P. A. J. Org. Chem.
1994, 59, 4042.
(10) Silverstein, R. M.; Webster, F. X. Spectrometric Identification of
Organic Compounds, 6th ed.; Wiley: New York, 1998.
10.1021/jo062370x CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/03/2007
J. Org. Chem. 2007, 72, 2647-2650
2647

SCHEME 1
The addition of TMEDA to the reaction mixtures gave higher
yields of the desired chalcogenorhodamine dyes. However, the
optimal conditions found for the generation of dianion 5 for
addition to chalcogenoxanthones 2 were the addition of 2.1
equiV of t-BuLi to 5-bromothiophene-2-carboxylic acid (12) and
0.25 equiV of TMEDA (relatiVe to 12) in anhydrous THF at
-78 °C to generate the dianion 5. A 4-fold excess of 5 was
then added to a solution of 2-O, 2-S, or 2-Se in THF at ambient
temperature. The reaction was stopped via the addition of AcOH
and then HPF6. The acids 7-9 (as the hexafluorophosphate salts,
Chart 1) were formed as a single regioisomer in the reaction
mixture and were isolated in 85, 84, and 79% yields, respec-
tively, following recrystallization.
SCHEME 2
Lithium-bromine exchange was also used to generate
3-lithiothiophene-2-carboxylate (6) from bromo carboxylic acid
13. Again, the optimal conditions for generation and reaction
of the dianion 6 with 2-S or 2-Se were identical to those above
for dianion 5: 2.1 equiv of t-BuLi and 0.25 equiv of TMEDA
1
relative to 13 in anhydrous THF at -78 °C. The H NMR
spectra of the crude reaction mixtures of rhodamine derivatives
10 and 11 showed a 32:1 mixture of the 9-(3-thienyl-2-
carboxylic acid) derivative 10 and the 2-thienyl-5-carboxylic
acid derivative 8 and a 40:1 mixture of the 9-(3-thienyl-2-
carboxylic acid) derivative 11 and the 2-thienyl-5-carboxylic
acid derivative 9. Both 10 and 11 were isolated as single
regioisomers in 68 and 58% yields, respectively, following
recrystallization.
The 3.6-Hz coupling constant observed between the thiophene
protons at the 3- and 4-positions of 7-9 and the 5.2-Hz coupling
constant observed between the thiophene protons at the 4- and
5-positions of 10 and 11 are consistent with the 2,5- and 2,3-
disubstituted thiophene groups, respectively.10 The high regi-
oselectiVity obserVed in these reactions suggests that dianions
5 and 6 maintain their regiochemical integrity during the
addition to chalcogenoxanthones 2.
Effect of TMEDA on Product Yields. In the reactions
described above, the number of equivalents of TMEDA
impacted the yields obtained from the addition of dianions 5
and 6 to the chalcogenoxanthones 2. While products were
observed with 1 equiv of TMEDA relative to the starting bromo
carboxylic acid 12 or 13 or 1 equiv of TMEDA relative to
t-BuLi, significantly higher yields were obtained using sub-
stoichiometric TMEDA (0.25 equiv relative to bromo carboxylic
acid). While this is an empirical observation on our part, the
use of substoichiometric amounts of TMEDA has been docu-
mented to accelerate directed metalation reactions in various
aromatic systems,11 which provides precedent for our observa-
tions.
Product Distributions Based on Relative Rates of Metal-
Halogen Exchange/Deprotonation. The use of metal-halogen
exchange to generate dianions 5 and 6 brings several different
reactions into competition. These reactions are summarized in
Scheme 1 for the conversion of 5-bromothiophene-2-carboxylic
acid (12) to dianion 5. If metal-halogen exchange in 12 were
fast relative to deprotonation, then 5-lithiothiophene-2-carboxylic
acid (14) would be the first-formed product and intermolecular
proton transfer would generate lithium thiophene-2-carboxylate
(15). However, if deprotonation of the carboxylic acid were fast
CHART 2
relative to metal-halogen exchange, then the lithium carboxy-
late 16 would be the first-formed product and metal-halogen
exchange in 16 would then give dianion 5. One probe of the
participation of each of these pathways is to quench the dianion
5 with D2O to give 2-deuterothiophene 17. The percentage of
deuterium incorporation would distinguish the extent of forma-
tion of 5 relative to 15. This type of analysis has been elegantly
used to evaluate comparative rates of metal-halogen exchange
relative to intra- and/or intermolecular proton (deuteron)
transfer.12
A third competitive reaction in Scheme 1 is the elimination
of HBr from the 2-bromo-2-methylpropane produced in the
metal-halogen exchange with t-BuLi. If this reaction is
comparable in rate or faster relative to metal-halogen exchange
or deprotonation, then the elimination reaction will be competi-
tive with these reactions, and, as described below, unreacted
12 should be isolated with t-BuLi as limiting reagent.
Similar reactions can be drawn for the reaction of bromo
carboxylic acid 13 (Scheme 2). One major difference in the
reaction pathways of 12 and 13 is that the 5-lithiothiophene-
2-carboxylic acid (14)sif formedsis unlikely to give intramo-
lecular proton-transfer relative to 3-lithiothiophene-2-carboxylic
acid (18) to give thiophene-2-carboxylate 15. From 18, the
formation of 15 would most likely be due to intramolecular
proton transfer. Deprotonation of 13 would generate lithium
carboxylate 19 and metal-halogen exchange in 19 would then
give dianion 6. Quenching the dianion 6 with D2O would give
3-deuterothiophene-2-carboxylate 20.
Following a D2O quench, an acidic workup would generate
thiophene-2-carboxylic acid (21) from 15, 5-deuterothiophene-
2-carboxylic acid (22) from 17, and 3-deuterothiophene-2-
carboxylic acid (23) from 20 (Chart 2). The ratio of 21 to 22/
23 provides a direct comparison of the rate of metal-halogen
(11) (a) Slocum, D. W.; Moon, R.; Thompson, J.; Coffey, D. S.; Li, J.
D.; Slocum, M. G.; Gayton-Garcia, R.; Siegel, A. Tetrahedron Lett. 1994,
35, 385. (b) Slocum, D. W.; Thompson, J.; Friesen, C. Tetrahedron Lett.
1995, 36, 8171.
(12) (a) Beak, P.; Musick, T. J.; Chen, C.-w. J. Am. Chem. Soc. 1988,
110, 3538-3542. (b) Gallagher, D. J.; Beak, P. J. Am. Chem. Soc. 1991,
113, 7984.
2648 J. Org. Chem., Vol. 72, No. 7, 2007

exchange and deprotonation of the carboxylic acid with t-BuLi.
The ratio of unreacted starting bromo acid 12 or 13 to 21-23
indicates the rate of HBr elimination from 2-bromo-2-methyl-
propane relative to metal-halogen exchange and deprotonation.
Relative Rate of HBr Elimination from 2-Bromo-2-
methylpropane. Bromo compounds 12 and 13 were treated with
2.1 equiv of t-BuLi as limiting reagent at -78 °C with 0.25-
2.0 equiv of TMEDA relative to the bromocarboxylic acid. The
resulting anions were quenched via the addition of the anion
solutions to stirred mixtures of THF/D2O at -78 °C, 0 °C, and
ambient temperature. The anions were also quenched via the
addition of D2O directly to the anion solutions at -78 °C. Once
quenched with D2O, the reaction mixtures were diluted with
saturated NaHCO3 and extracted with ether. The aqueous phase
was acidified with HCl and reextracted with ether to isolate
the carboxylic acids in >90% yields.
of relatively unsolvated DO- might accelerate the elimination
of HBr by either 5 or DO- (to generate HOD, which could
then act as a proton source). To investigate this possibility, 12
was treated with 2.1 equiv of s-BuLi as limiting reagent at
-78 °C with 0.25 of TMEDA relative to 12. The dianion 5
was quenched via the addition of D2O directly to the anion
solution at -78 °C to give (99 ( 2)% incorporation of deuterium
and a (53 ( 2)/(47 ( 2) ratio of 22 to 23. The reduced reactivity
of 2-bromobutane (produced in the metal-halogen exchange
with s-BuLi) relative to 2-bromo-2-methylpropane toward
elimination of HBr is consistent with the observed results.
Quenching Dianion 6 with D2O. The addition of the
products from the reaction of 3-bromothiophene-2-carboxylic
acid (13) with 2.1 equiv of t-BuLi to THF/D2O at 0 °C showed
(99 ( 3)% incorporation of one deuterium by 1H NMR to give
a (48 ( 2)/(52 ( 2) ratio of 22 to 23. The addition of D2O to
the anion had no impact on the 22/23 ratio, suggesting
equilibrium is rapidly attained upon exposure to D2O. The
addition of the 13/t-BuLi mixture immediately after mixing of
reagents at -78 °C to chalcogenoxanthones 2 at ambient
temperature gave products from the addition of dianion 6 with
>30:1 regioselectivity suggesting that 6 is relatively stable to
the conditions of reaction. These results also suggest that
5-deuterothiophene-2-carboxylic acid 21 is primarily formed
from reactions of 6 during the D2O quench.
Reactions of bromothiophene-2-carboxylic acids 12 and 13
with 2.1 equiV of t-BuLi returned no trace of unreacted 12 or
1
13 by H NMR. These results indicate that elimination of HBr
from the 2-bromo-2-methylpropane with t-BuLi (or any other
“base” generated during reaction) is slow relative to metal-
halogen exchange and deprotonation of the carboxylic acid; i.e.,
both of these reactions are complete and consume the t-BuLi.
Furthermore, the reaction of dianion 5 or 6 with 2-bromo-2-
methylpropane must also be relatively slow.
The addition of D2O directly to the 13/t-BuLi reaction mixture
gave (78 ( 3)% incorporation of deuterium, which again
suggests an endogenous proton source. 2-Bromo-2-methylpro-
pane was identified as the likely proton source by treating 13
with 2.1 equiv of sec-BuLi as limiting reagent at -78 °C with
0.25 of TMEDA relative to 13. The dianion 6 was quenched
via the addition of D2O directly to the anion solution at
-78 °C to give (100 ( 2)% incorporation of deuterium and a
(29 ( 2)/(71 ( 2) ratio of 22 to 23.
Effect of Temperature and TMEDA on Product Ratios
from the Addition of Dianions 5 and 6 to THF/D2O
Mixtures. In the D2O quenching experiments described above,
the temperature of the THF/D2O quench and the number of
equivalents of TMEDA had minimal impact on product ratios.
For dianion 5, which was most sensitive to conditions, the 22:
23 ratio varied over the range (76-82)/(24-18) as a function
of temperature (0 °C, -78 °C, ambient) and over the range (74-
82)/(26-18) for 0-2.0 equiv of TMEDA relative to bromo
carboxylic acid (12).
Kinetic Accessibility and Steric Interactions. Dianions 5
and 6 maintained their regiochemistry during addition to
chalcogenoxanthones 2. When one compares the nearly 1:1 ratio
of 22 to 23 formed from the quenching of dianion 6 with D2O
and the 4:1 ratio of 22 to 23 from the quenching of dianion 5,
one is drawn to the conclusion that the 5-position is kinetically
more accessible to deprotonation than the 3-position in thiophene-
2-carboxylic acid (21) under the quenching conditions. The
observation that dianion 6 is formed by treating thiophene-2-
carboxylic acid (21) with 2 equiv of the relatively unhindered
n-BuLi while dianion 5 is formed with 2 equiv of the hindered
base LDA7 is consistent with this argument.
The use of s-BuLi in the synthetic reactions generated dianion
6 unambiguously from 3-bromothiophene-2-carboxylic acid
(13), but gave mixtures of 5 and 6 when bromo carboxylic acid
12 was treated with 2.1 equiv of s-BuLi. The addition of the
12/s-BuLi reaction mixture (conditions identical to the 12/t-
BuLi reaction) to 2-S gave a 3:1 mixture of 11/8. Deprotonation
Quenching Dianion 5 with D2O. The D2O quench of the
products from the reaction of bromothiophene carboxylic acid
12 with 2.1 equiv of t-BuLi and 0.25 equiv of TMEDA (relative
to 12) showed (100 ( 2)% incorporation of one deuterium by
1H NMR to give an (82 ( 2)/(18 ( 2) ratio of 22 to 23
(Chart 2). In the synthetic studies, dianion 5 only gave the 9-(2-
thienyl-5-carboxy)rhodamine derivatives 7-9. No products were
detected in the crude reaction mixture from dianion 6, which
suggests that 5 is stable under the conditions of reaction.
Consequently, it is logical that 23 must be formed during the
D2O quench of 5. While 22 arises directly from the D2O quench
of dianion 5, 23 most likely arises from proton transfer to
dianion 5 to give carboxylate 15. The subsequent reaction of
either 15 or 21 with residual t-BuLi or with dianion 5 could
generate dianion 6, which would produce 23 via the D2O
quench. Isotope ratios from mass spectrometry data are con-
sistent with the incorporation of a single deuterium in the
thiophene-2-carboxylic acids while the thiophene protons in the
1H NMR spectra of the product mixtures all show doublet
multiplicity, which is again consistent with monodeuterated
species.
The real question is whether dianion 6 is formed during the
initial reaction of 12 with t-BuLi or whether carboxylic acid
23 is formed during the D2O quench. In similar reactions,
metal-halogen exchange, protonation, and deprotonation have
been more rapid than mixing of reagents.13 The inverse addition
of D2O to the 12/t-BuLi mixture at -78 °C gave (77 ( 3)%
incorporation of deuterium and a (68 ( 2)/(32 ( 2) ratio of 22
to 23. The increase in the “rearranged” product again supports
the idea that dianion 6 is generated during the D2O quench.
The decreased deuteration when D2O is added to the dianion
suggests an endogenous proton source in the reaction such as
the 2-bromo-2-methylpropane generated during metal-halogen
exchange. Local heating upon addition of D2O or the generation
(13) Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1975, 40,
2394.
J. Org. Chem, Vol. 72, No. 7, 2007 2649

J ) 2.4 Hz), 7.29 (d, 1 H, J ) 3.6 Hz), 6.95 (dd, 2 H, J ) 2.4,
9.6 Hz), 3.21 (s, 12 H); 13C NMR (125 MHz, CD3CN) δ 162.7,
154.1, 152.7, 145.9, 144.5, 138.3, 137.0, 134.7, 132.3, 120.9, 116.4,
110.1, 41.1; λmax (H2O) 603 nm (ꢀ 53 000 M-1 cm-1); HRMS (ESI)
m/z 457.0487 (calcd for C22H21N2O2S80Se 457.0483). Anal. Calcd
for C22H21N2O2SSe‚PF6: C, 43.94; H, 3.52; N, 4.66. Found: C,
44.05; H, 3.72; N, 4.99.
For 10: 68%; mp 294-295 °C; 1H NMR (400 MHz, CD2Cl2) δ
7.61 (d, 1 H, J ) 5.2 Hz), 7.46 (d, 2 H, J ) 9.2 Hz), 6.96 (d, 2 H,
J ) 2.4 Hz), 6.92 (d, 1 H, J ) 5.2 Hz), 6.86 (dd, 2 H, J ) 2.4,
9.2 Hz), 3.18 (s, 12 H); 13C NMR (75 MHz, CD3CN) δ 162.3,
157.2, 154.7, 144.6, 142.2, 136.1, 134.2, 133.2, 131.8, 119.5, 116.6,
106.6, 41.0; λmax (H2O) 574 nm (ꢀ 5.4 × 104 M-1 cm-1); HRMS
(ESI) m/z 409.1031 (calcd for C22H21N2O2S2 409.1039). Anal. Calcd
for C22H21N2O2S2‚PF6: C, 47.65; H, 3.82; N, 5.05. Found: C,
47.29; H, 4.16; N, 4.88.
For 11: 58%; mp 283-284 °C; 1H NMR (400 MHz, CD2Cl2) δ
7.61 (d, 1 H, J ) 5.2 Hz), 7.46 (d, 2 H, J ) 9.2 Hz), 6.96 (d, 2 H,
J ) 2.4 Hz), 6.92 (d, 1 H, J ) 5.2 Hz), 6.86 (dd, 2 H, J ) 2.4,
9.2 Hz), 3.18 (s, 12 H); 13C NMR (75 MHz, CD3CN) δ 162.2,
158.4, 154.2, 145.9, 144.0, 137.9, 134.3, 132.3, 132.0, 120.1, 116.2,
110.0, 41.0; λmax (H2O) 584 nm (ꢀ 8.4 × 104 M-1 cm-1); HRMS
(ESI) m/z 409.1031 (calcd for C22H21N2O2S80Se: 457.0483). Anal.
Calcd for C22H21N2O2SSe‚PF6: C, 43.94; H, 3.52; N, 4.66.
Found: C, 44.14; H, 3.59; N, 4.72.
at C-3 may be competitive with metal-halogen exchange when
s-BuLi is used.
In summary, the addition of dianions 5 and 6 (Chart 1),
generated by lithium-bromine exchange with t-BuLi, to chal-
cogenoxanthones 2 provides a general route to rhodamine
derivatives bearing a 9-(2-thienyl-5-carboxy) or 9-(3-thienyl-
2-carboxy) substituent. Addition of 0.25 equiv of TMEDA
during generation of the dianions 5 and 6 from bromothiophene-
2-carboxylic acids 12 and 13 at -78 °C gives species that (1)
have sufficient reactivity to add to chalcogenoxanthones 2 at
ambient temperature and (2) maintain their regiochemistry upon
addition to solutions of the chalcogenoxanthones 2. The
substoichiometric levels of TMEDA required for reaction
suggest that 2:2 complexes of TMEDA and organolithium
reagents are not optimal in these reactions.14
Quenching studies with D2O indicate that elimination of HBr
from 2-bromo-2-methylpropane generated from metal-halogen
exchange with t-BuLi is slow relative to metal-halogen
exchange and deprotonation using bromo carboxylic acids 14,
19, and 20. Bromothiophene-2-carboxylic acids 12 and 13 are
completely converted to dianions 5 and 6, respectively, with
2.1 equiv of t-BuLi. An additional equiV of t-BuLi is not required
in these reactions to scaVenge HBr from 2-bromo-2-methyl-
propane. The high regioselectivity observed in the reactions of
dianions 5 and 6 is consistent with rapid deprotonation of the
carboxylic acid substituents of 12 and 13 followed by metal-
halogen exchange.
Generation of Dianions 5 and 6. A. With tert-Butyllithium
Followed by Quenching with D2O. t-BuLi (1.7 M in hexanes,
3.3 mL, 5.6 mmol), TMEDA (81 mg, 0.70 mmol to 0.32 g,
0.28 mmol), and bromo carboxylic acid 12 or 13 (0.56 g, 2.7 mmol)
were treated as described above at -78 °C. Following addition,
the resulting solution was immediately transferred via cannula to a
stirred mixture of 7 mL of THF and 1.0 mL (55 mmol) of D2O
cooled to -78 or 0 °C or at ambient temperature. Alternatively,
the dianion was quenched at -78 °C via the addition of 200 µL
(11 mmol) of D2O. The D2O-quenched mixtures were stirred with
10 mL of saturated NaHCO3 solution and extracted with ether
(2 × 10 mL). The aqueous layer was acidified via the dropwise
addition of concentrated HCl, the resulting solution was extracted
with ether (2 × 15 mL), and these extracts were dried over Na2-
SO4 and concentrated. The yields of recovered of carboxylic acids
Experimental Section
General Procedure for Generation of Chalcogenorhodamines
7-11. t-BuLi (1.7 M in hexanes, 3.3 mL, 5.6 mmol) was added
dropwise to a stirred solution of 5-bromothiophene-2-carboxylic
acid (12) or 3-bromothiophene-2-carboxylic acid (13, 2.7 mmol)
and TMEDA (81 mg, 0.70 mmol) in 25 mL of anhydrous THF at
-78 °C. The resulting solution was immediately transferred via
cannula to the chalcogenoxanthones 2 (0.67 mmol) dissolved in
7 mL of anhydrous THF at ambient temperature. The resulting
mixture was heated at reflux for 12 min. Acetic acid (0.33 g,
5.6 mmol) was added, and the reaction mixture was poured into a
10% by wt. solution of aqueous HPF6. The precipitate was collected
after 1.0 h of stirring and washed with water and ether. The final
dyes were obtained following recrystallization from CH3CN/Et2O.
For 7: 85%; mp 280-282 °C; 1H NMR (400 MHz, CD3CN) δ
7.95 (d, 1 H, J ) 3.6 Hz), 7.58 (d, 2 H, J ) 9.6 Hz), 7.38 (d, 1 H,
J ) 3.6 Hz), 7.04 (dd, 2 H, J ) 1.6, 9.6 Hz), 6.82 (d, 2 H, J )
1.6 Hz), 3.26 (s, 12 H); 13C NMR (75.5 MHz, DMSO-d6) δ 162.4,
156.9, 156.8, 147.9, 139.4, 136.3, 133.1, 132.8, 130.9, 115.0, 113.1,
96.4, 40.6; λmax (H2O) 571 nm (ꢀ 57 000 M-1 cm-1); HRMS (ESI)
m/z 393.1270 (calcd for C22H21N2O3S 393.1273). Anal. Calcd for
C22H21N2O3S‚PF6: C, 49.07; H, 3.93; N, 5.20. Found: C, 48.77;
H, 4.36; N, 5.22.
1
were >90%. The H NMR spectra of the residues were acquired
at 500 MHz in CDCl3 using residual CHCl3 as an internal standard
and integrals were carefully measured for the following signals in
thiophene-2-carboxylic acid: δ 7.89 (H-3), 7.635 (H-5), 7.125
(H-4) (1H NMR spectrum in the Supporting Information). Integral
values reported are the of average triplicate runs with three
independent FIDs for values in each individual run with ( the
standard deviation.
B. With sec-Butyllithium Followed by Quenching with D2O.
s-BuLi (0.95 M in cyclohexanehexanes, 6.0 mL, 5.7 mmol) was
added dropwise to a stirred solution 12 or 13 (0.56 g, 2.7 mmol)
and TMEDA (81 mg, 0.70 mmol) in 25 mL of anhydrous THF at
-78 °C. The solution of dianion was quenched at -78 °C via the
addition of 200 µL of D2O (11 mmol). The deuterated thiophene-
2-carboxylic acids were isolated as described above.
For 8: 84%; mp 182-184 °C; 1H NMR (400 MHz, CD3CN) δ
7.93 (d, 1 H, J ) 3.6 Hz), 7.55 (d, 2 H, J ) 9.6 Hz), 7.27 (d, 1 H,
J ) 2.8 Hz), 7.19 (d, 2 H, J ) 2.8 Hz), 7.03 (dd, 2 H, J ) 2.8,
9.6 Hz), 3.23 (s, 12 H); 13C NMR (125 MHz, CD3CN) δ 162.7,
154.6, 151.4, 144.7, 142.8, 137.3, 136.4, 134.7, 132.5, 120.3, 116.8,
106.7, 41.1; λmax (H2O) 591 nm (ꢀ 54 000 M-1 cm-1); HRMS (ESI)
m/z 409.1040 (calcd for C22H21N2O2S2 409.1039). Anal. Calcd for
C22H21N2O2S2‚PF6: C, 47.65; H, 3.82; N, 5.05. Found: C, 47.69;
H, 3.95; N, 5.36.
Acknowledgment. We thank Prof. Peter Beak (University
of Illinois) for helpful comments and suggestions. This research
was supported in part by the Department of Defense (Breast
Cancer Research Program) Award No. W81XWH-04-1-0368
to M.K.G.
Supporting Information Available: General experimental and
1H NMR spectra of thiophene-2-carboxylic acid and deuterated
acids generated by the quenching of 5 and 6 with D2O. This material
is available free of charge via the Internet at http://pubs.acs.org.
For 9: 79%; mp 232-234 °C; 1H NMR (400 MHz, CD3CN) δ
7.91 (d, 1 H, J ) 3.6 Hz), 7.56 (d, 2 H, J ) 9.6 Hz), 7.41 (d, 2 H,
(14) (a) Stratakis, M. J. Org. Chem. 1997, 62, 3024. (b) Rennels, R. A.;
Maliakal, A. J.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 421.
JO062370X
2650 J. Org. Chem., Vol. 72, No. 7, 2007