Improved synthesis of 3-substituted-4-amino-[3,2-c]-thienopyridines

Article abstract of DOI:10.1021/jo9003772

(Chemical Equation Presented) Two syntheses of 3-substituted-4-amino-[3,2- c]thienopyridines have been developed to replace the standard literature route to these compounds, which uses unattractive conditions involving azide and high temperatures. The fir

Full text of DOI:10.1021/jo9003772

Improved Synthesis of 3-Substituted-4-amino-[3,2-c]-thienopyridines
Kenneth M. Engstrom,* Amanda L. Baize, Thaddeus S. Franczyk, Jeffrey M. Kallemeyn,
Mathew M. Mulhern, Robert C. Rickert, and Seble Wagaw
Global Pharmaceutical R&D, Process Research & DeVelopment, Abbott Laboratories, 1401 Sheridan
Road, North Chicago, Illinois 60064-6290
kenneth.engstrom@abbott.com
ReceiVed February 19, 2009
Two syntheses of 3-substituted-4-amino-[3,2-c]thienopyridines have been developed to replace the standard
literature route to these compounds, which uses unattractive conditions involving azide and high
temperatures. The first synthesis utilizes a Friedel-Crafts reaction as its key ring-forming step, whereas
the second route relies on an unprecedented intramolecular reductive cyclization between a nitroolefin
and a nitrile as its key ring-forming step. The development and optimization of each 3-substituted-4-
amino-[3,2-c]thienopyridine synthesis is discussed and a comparison of the routes is presented.
Introduction
form the pyridine ring as the key step. Although these reactions
provide an acceptable yield of 3-bromo-4-hydroxy-[3,2-c]-
thienopyridine 3, several factors limit its scalability. The product
3 is unstable under the reaction conditions; a 20% decrease in
product concentration is seen in 30 min in diphenyl ether at
250 °C.6,7 In addition, the use of sodium azide in this sequence
presents safety and environmental concerns because of its
toxicity, shock-sensitivity, and explosiveness near 300 °C.
Because of the difficulties surrounding the scalability of the
thermal route and faced with the prospect of larger material
demands, we sought alternative routes to 3-substituted-4-amino-
[3,2-c]-thienopyridine 1.
Thienopyridines are pharmacophores present in a variety of
pharmaceutical targets for multiple indications.1 As part of our
multitarget kinase oncology program, we required the synthesis
of 3-substituted-4-amino-[3,2-c]-thienopyridine 1.2 Although the
synthesis of [3,2-c]-thienopyridine itself has been known for
over 50 years, it remains one of the more difficult thienopyridine
isomers to synthesize.3 Of the few published routes to [3,2-c]-
thienopyridines substituted with a heteroatom at the 4-position,
most are relatively low yielding or install difficult to remove
functionality at the 6-position.4
The thermal route shown in Scheme 1 relies on bond
formation between C-9 and C-4 as the key ring closure step,
but bond formation between other atoms of the resulting
thienopyridine to effect ring closure has been precedented.
In particular, intramolecular Friedel-Crafts reaction between
(3) For a review on the synthesis of thienopyridines, see ref 1. Barker, J. M.
AdV. Heterocycl. Chem. 1977, 21, 65–118.
(4) (a) Ikeura, Y.; Tanaka, T.; Kiyota, Y.; Morimoto, S.; Ogina, M.; Ishimaru,
T.; Kamo, I.; Doi, T.; Natsugari, H. Chem. Pharm. Bull. 1997, 45, 1642–1652.
(b) Molina, P.; Fresneda, P. M.; Hurtado, F. Synthesis 1987, 1, 45–48. (c) Farnier,
M.; Soth, S.; Fournari, P. Can. J. Chem. 1976, 54, 1066–1073.
(5) (a) New, J. S.; Christopher, W. L.; Yevich, J. P.; Butler, R.; Schlemmer,
R. F.; VanderMaelen, C. P.; Cipollina, J. A. J. Med. Chem. 1989, 32, 1147–
1156. (b) Eloy, F.; Deryckere, A. Bull. Soc. Chim. Belges 1970, 79, 301–312.
(6) For the use of catalytic iodine to lower the isomerization reaction
temperature, see: (a) Miyazaki, Y.; Nakano, M.; Sato, H.; Truesdale, A. T.; Stuart,
J. D.; Nartey, E. N.; Hightower, K. E.; Kane-Carson, L. Bioorg. Med. Chem.
Lett. 2007, 17, 250–254.
The route most applicable to the synthesis of 1, which we
have labeled the “thermal route”, is shown in Scheme 1 and
has been previously described.5-7 This route relies on the
thermal isomerization and cyclization of a vinyl isocyanate to
(1) Litvinov, V. P.; Dotsenko, V. V.; Krivokolysko, S. G. AdV. Het. Chem.
2007, 93, 117–178.
(2) Heyman, H. R.; Frey, R. R.; Bousquet, P. F.; Cunha, G. A.; Moskey,
M. D.; Ahmed, A. A.; Soni, N. B.; Marcotte, P. A.; Pease, L. J.; Glaser, K. B.;
Yates, M.; Bouska, J. J.; Albert, D. H.; Black-Schaefer, C. L.; Dandliker, P. J.;
Stewart, K. D.; Rafferty, P.; Davidsen, S. K.; Michaelides, M. R.; Curtin, M. L.
Bioorg. Med. Chem. Lett. 2007, 17, 1246–1249.
(7) For the use of tributylamine as an additive, see: (a) Abbott, L.;
Betschmann, P.; Burchat, A.; Calderwood, D. J.; Davis, H.; Hrnciar, P.; Hirst,
G. C.; Li, B.; Morytko, M.; Mullen, K.; Yang, B. Bioorg. Med. Chem. Lett.
2007, 17, 1167–1171.
10.1021/jo9003772 CCC: $40.75
Published on Web 04/16/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3849–3855 3849

Engstrom et al.
SCHEME 1
SCHEME 2
SCHEME 4
SCHEME 3
key intermediates can be synthesized from 9, which is
accessible from commercially available 3,4-dibromothiophene
by metal-halogen exchange and quenching with carbon
dioxide.11
Results and Discussion
Friedel-Crafts Route. Synthesis of 6 via the Friedel-Crafts
route (Scheme 4) began with coupling of bromoacid 9 with
aminoacetaldehyde dimethylacetal via the acid chloride,
which provided the Friedel-Crafts substrate 10 in 82% yield.
Screening of a multitude of Bronsted and Lewis acids to
effect cyclization of 10 resulted mostly in complex mixtures
containing little or no desired product 3. Aluminum trichlo-
ride (4.0 equiv) and a substoichiometric amount of acetic
acid (0.67 equiv) afforded a modest yield of 41%. However,
equivalents of aluminum trichloride and acetic acid had to
be carefully controlled to prevent complete decomposition
and workup to remove aluminum byproducts was tedious.
a dimethyl acetal and the thiophene ring, which constitutes
bond formation between C-7 and C-8, has been demonstrated
in the synthesis of unsubstituted [3,2-c]-thienopyridine
(Scheme 2, eq 1).8 Intramolecular reductive cyclization
between a nitroarene and an aldehyde, which constitutes bond
formation between N-5 and C-4, has been demonstrated in
the synthesis of thieno-[3,2-c]-isoquinoline N-oxide (Scheme
2, eq 2).9 Acid-catalyzed intramolecular addition of an imine/
enamine to a nitrile, which also constitutes bond formation
between N-5 and C-4, has been demonstrated in the synthesis
of a 6-substituted-6,7-dihydro-4-amino-[3,2-c]-thienopyridine
(Scheme 2, eq 3).10
Better results were obtained by running the Friedel-Crafts
cyclization in polyphosphoric acid (PPA). Using 115% PPA,
the yield of 3 was improved to 63%, with the major impuri-
ty being 16 peak area percent of oxazole 11 as determined by
HPLC analysis. The amount of oxazole was reduced to 2% by
using 105% PPA. The product could be crystallized directly
Applying these disconnections to the 3-substituted-4-
amino-[3,2-c]-thienopyridine 1 leads to the retrosyntheses
shown in Scheme 3. The “Friedel-Crafts route” would go
through key intermediate 7 while the “reductive cyclization
route” would go through key intermediate 8. Both of these
(8) (a) Wikel, J. H.; Denney, M. L.; Vasileff, R. T. J. Heterocyclic Chem.
1993, 30, 289–290. (b) Herz, W.; Tsai, L. J. Am. Chem. Soc. 1953, 75, 5122–
5123.
(9) Gronowitz, S.; Timari, G. J. Het. Chem. 1990, 27, 1127–1129.
(10) Beaton, H.; Hamley, P.; Tinker, A. C. Tetrahedron Lett. 1998, 39, 1227–
1230.
(11) (a) Steinkopf, W.; Jacob, H.; Penz, H. Just. Leib. Ann. Der Chem. 1934,
512, 136–156. (b) Lawesson, S. Ark. Kemi 1957, 11, 325–336. (c) Hawkins,
D. W.; Iddon, B.; Longthorne, D. S.; Rosyk, P. J. J. Chem. Soc. Perkin Trans.
1 1994, 19, 2735–2744.
3850 J. Org. Chem. Vol. 74, No. 10, 2009

3-Substituted-4-amino-[3,2-c]-thienopyridines
from the reaction mixture by addition of water to give a 74%
isolated yield of 3.
acetic anhydride as the dehydrating agent. Nitroalkene 16 was
isolated in 91% yield by simply filtering the crystallized product
from the crude reaction mixture.
The key step in this route is reductive cyclization of 16 to 6.
While intramolecular reductive cyclization between nitroarenes
and nitriles to form aminopyridines is well precedented (vide
infra), there were no known examples of this type of intramo-
lecular reductive cyclization where the nitroarene is replaced
with an R,ꢀ-unsaturated nitroalkene. However, we hoped that
a judicious choice of reagents and conditions might bring about
the desired transformation.
Since intermediate 3 is common to both the Friedel-Crafts
route and the thermal route shown in Scheme 1, the same
chemistry can be used to complete the synthesis of 6 in 65%
yield over the three steps. The overall yield of 6 from 9 utilizing
the Friedel-Crafts cyclization route was 42% for five steps.
Reductive cyclization of 16 using trimethylphosphite provided
no desired product.14 Zinc-catalyzed reductive cyclization using
ammonium formate or formic acid also failed.15 An excess of
iron in acetic acid afforded trace amounts of product, but it was
accompanied by extensive formation of numerous unidentified
side products.16 Although palladium-catalyzed reductive cy-
clization in acetic acid using formate salts17 or molecular
hydrogen gave full conversion of 16, these reactions were low
yielding (30-50% assay yields) due to extensive side product
formation.
SCHEME 5
Reductive Cyclization Route. Synthesis of 6 via the reduc-
tive cyclization route began with synthesis of bromonitrile 13
(Scheme 5).12,13 Acid 9, which was previously used in the
Friedel-Crafts route, was converted to the acid chloride using
thionyl chloride and catalytic DMF in THF. Quenching into
concentrated aqueous ammonia, extractive workup, and crystal-
lization from ethyl acetate and heptane gave amide 12 in 71%
isolated yield.11b Dehydration of this amide to the nitrile with
thionyl chloride proceeded smoothly in DMF and the product
was isolated in 87% yield simply by addition of the crude
reaction mixture to water.
Suzuki cross-coupling between 13 and t-butyl-4-(4,4,5,5,-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate under bi-
phasic conditions proceeded to greater than 99% conversion.
A purification sequence of carbon treatment, chromatography,
and recrystallization provided pure 14 in 80% isolated yield
(Scheme 6). Regioselective deprotonation of 14 using 2.5 equiv
of LDA followed by DMF quench installed the aldehyde
functional group alpha to the nitrile. Following aqueous workup,
chromatography, and crystallization, the isolated yield of 15 was
85%. Aldehyde 15 was then homologated to the R,ꢀ-unsaturated
nitroalkene by way of a DMAP-catalyzed Henry reaction using
It was finally discovered that tin (II) dichloride dihydrate
smoothly reduced and cyclized the nitroalkene to N-oxide
17.18,19 However, removal of the tin byproducts turned out to
be more difficult than anticipated. After much experimentation,
it was discovered that a solvent switch from ethyl acetate to
methanol and treatment with aqueous potassium carbonate
delivered a filterable precipitate that was a mixture of N-oxide
17 and tin oxide. Repeated slurrying of the precipitate in
methanol followed by filtration resulted in a methanol solution
of N-oxide 17 free of tin oxide. This solution was further reacted
with molecular hydrogen, palladium on carbon, and substo-
ichiometric acetic acid to give the target molecule 6 in 84%
yield over the two steps.
While this two step reductive cyclization utilizing tin (II)
dichloride dihydrate gave a good yield of the desired product
6, the sequence was hampered by the tedious removal of tin
oxide. This led us to further explore metal-catalyzed reductive
cyclization using molecular hydrogen because of the ease with
which the catalyst, excess reagent, and byproducts can be
removed.
SCHEME 6
J. Org. Chem. Vol. 74, No. 10, 2009 3851

Engstrom et al.
was added. The homogeneous solution was heated to 100 °C for
22 h, at which point 97% conversion of 4-bromothiophene-2-
carbaldehyde was achieved as determined by HPLC analysis. The
reaction was cooled to 50 °C and about half of the solvent was
removed via rotary evaporation. Water (1900 mL) was added
followed by 6 M aqueous hydrochloric acid (650 mL) to adjust
the pH from 6 to 2 as determined by pH indicating strips. After
one hour the solids were filtered and washed with a minimal amount
of water. The wet cake was transferred to a 2 L round-bottom flask.
Ethanol (475 mL) and water (375 mL) were added and the slurry
was heated to 80 °C to dissolve the solids. The solution was cooled
to 35 °C over 80 min. The solids were filtered and washed with a
minimal amount of water. The wet cake was dried at 50 °C and 20
in. Hg to afford 2 (190.86 g, 81.9%) as a tan crystalline solid
contaminated with 3% 4-bromothiophene-2-carbaldehyde as de-
It was eventually found that a one-pot reductive cyclization
of 16 to 6 using molecular hydrogen could be accomplished
using a vanadium and hypophosphorous acid modified platinum
on carbon catalyst.20 Filtration to remove the catalyst followed
by aqueous workup and chromatography provided 6 in 76%
yield. Utilizing this operationally simpler reductive cyclization,
the overall yield of 6 from 9 was 29% for six steps.
TABLE 1. Comparison of Three Routes to 6
route
isolations
chromatographies
yield
thermal
Friedel-Crafts
reductive cyclization
5
5
6
1
1
3
41%
42%
29%
1
1
termined by H NMR. Mp 154-156 °C; H NMR (400 MHz,
(CD3)SO) δ: 7.78 (m, 1H), 7.65 (dt, J ) 15.7, 0.7 Hz, 1H), 7.54
(m, 1H), 6.24 (d, J ) 15.7 Hz) ppm. 13C NMR (100 MHz, (CD3)SO)
δ: 166.4, 139.7, 134.9, 132.2, 126.2, 118.6, 109.6 ppm. HRMS
(ESI) for C7H6BrO2S (M + H+) calcd 232.92664 found 232.92665.
3-Bromo-4-hydroxy-[3,2-c]-thienopyridine (3). To a 2 L round-
bottom flask equipped with a 50% NaOH scrubber was charged 2
(166.06 g, 0.712 mol, 1.00 equiv) and chloroform (1315 mL). DMF
(6.6 mL, 85.2 mmol, 0.12 equiv) and thionyl chloride (62.0 mL,
0.850 mol, 1.20 equiv) were added. The reaction was heated to
reflux for one hour and cooled to 50 °C. The solvent was removed
via rotary evaporation to give crude trans-3-(4-bromothiophen-2-
yl)-acryloyl chloride.
To a 1 L Erlenmeyer flask was charged sodium azide (63.3 g,
0.974 mol, 2.0 equiv) followed by water (245 mL) and p-dioxane
(245 mL). A solution of crude trans-3-(4-bromothiophen-2-yl)-
acryloyl chloride (233.66 g of 47.6 wt% material, 122.55 g, 0.487
mol, 1.0 equiv) in p-dioxane (245 mL) was added to the 1 L
Erlenmeyer flask and stirred at ambient temperature for 2.5 h. The
mixture was transferred to a separatory funnel and the bottom
organic layer was separated. The upper aqueous layer was washed
twice with ethyl acetate (120 mL each wash). The combined
organics were dried over magnesium sulfate (60 g), filtered, and
concentrated. The solids were dissolved with dichloromethane (340
mL) to give a solution of approximately 1.2 M trans-3-(4-
bromothiophen-2-yl)-acryloyl azide.
To a 500 mL round-bottom flask was charged diphenyl ether
(70 mL), which was heated to 255 °C. A solution of trans-3-(4-
bromothiophen-2-yl)-acryloyl azide (85 mL of an approximately
1.2 M solution in dichloromethane, 0.10 mol) was added over 10
min, maintaining an internal temperature above 250 °C. The
dichloromethane flashed off with an accompanying large noise. The
reaction was stirred at 250 °C for 5 min and then cooled to 90 °C.
A 1:1 mixture of diethyl ether and heptane (350 mL) was added.
The slurry was cooled to ambient temperature and stirred for 30
min. The solids were filtered, the wet cake washed with a 1:1
mixture of diethyl ether and heptane (350 mL), and the solids dried
at 50 °C and 20 in. Hg to afford 3 (17.13 g, 72% from 2) as a tan
crystalline solid. Mp > 225 °C; 1H NMR (400 MHz, (CD3)SO) δ:
11.45 (br s, 1H), 7.64 (d, J ) 0.6 Hz, 1H), 7.25 (d, J ) 7.0 Hz,
1H), 6.85 (d, J ) 7.0 Hz, 1H) ppm. 13C NMR (100 MHz, (CD3)SO)
δ: 157.3, 148.6, 130.3, 124.5, 122.4, 106.6, 100.8 ppm. HRMS
(ESI) for C7H5BrNOS (M + H+) calcd 229.92697 found 229.92741.
3-Bromo-4-chloro-[3,2-c]-thienopyridine (4). To a 1 L round-
bottom flask was charged 3 (38.0 g, 165 mmol, 1.0 equiv) followed
by POCl3 (101 mL, 1.09 mol, 6.6 equiv). The slurry was heated to
75 °C (internal temperature) for one hour. The reaction was cooled
to ambient temperature and dichloromethane (600 mL) was added.
The organic solution was added dropwise to water (1400 mL) while
keeping the temperature around 25 °C. The reaction flask was rinsed
once with dichloromethane (400 mL). The biphasic solution was
filtered through Celite and washed once with dichloromethane (200
mL). The layers were separated and the aqueous layer extracted
once with dichloromethane (300 mL). The combined organics were
Conclusions
A summary of the three routes to 6 is shown in Table 1.
Although the thermal route and the Friedel-Crafts route have
similar step counts and overall yields, the thermal route has
several flaws that make it unattractive for scale up, including
the use of azide and the instability of 3 under the reaction
conditions used to make it. While the reductive cyclization route
is longer and lower yielding than the thermal route, it also avoids
both of these pitfalls. When comparing the Friedel-Crafts and
reductive cyclization routes to each other, it is clear that the
Friedel-Crafts route is superior in terms of isolations and yield,
as well as relative simplicity of the reagents used throughout
the sequence. However, the reductive cyclization route is a novel
method for accessing 3-substituted-4-amino-[3,2-c]-thienopy-
ridine compounds and may prove valuable for targets for which
the Friedel-Crafts chemistry fails.21 In the end, both routes
clearly overcome the major shortcomings of the thermal route
and offer new alternatives for the synthesis of 3-substituted-4-
amino-[3,2-c]-thienopyridine compounds.
Experimental Section
trans-3-(4-Bromothiophen-2-yl)-acrylic Acid (2). To a 2 L
round-bottom flask was charged 4-bromothiophene-2-carbaldehyde
(191.04 g, 1.00 mol, 1.00 equiv) and malonic acid (124.9 g, 1.20
mol, 1.20 equiv) followed by pyridine (750 mL). The reaction was
heated to 80 °C and piperidine (11.9 mL, 0.120 mol, 0.10 equiv)
(12) For a one-step synthesis of 13 from 3,4-dibromothiophene using copper
(I) cyanide, see: Gonzalez, I. C.; Davis, L. N.; Smith, C. K. Bioorg. Med. Chem.
Lett. 2004, 14, 4037–4043.
(13) For a three-step synthesis of 13 from 3,4-dibromothiophene involving
dehydration of 4-bromothiophene-3-carbaldehyde oxime, see: Fournari, P.;
Guillard, R.; Person, M. Bull. Chim. Soc. Fr. 1967, 11, 4115–4120.
(14) Kametani, T.; Yamanaka, T.; Ogasawara, K. J. Chem. Soc. C 1969,
385–387.
(15) Gowda, D. C.; Mahesh, B.; Gowda, S. Indian J. Chem. 2001, 40B, 75–
77.
(16) (a) Hamid, A.; Elomri, A.; Daich, A. Tetrahedron Lett. 2006, 47, 1777–
1781. (b) Wang, Y. D.; Boschelli, D. H.; Johnson, S.; Honores, E. Tetrahedron
2004, 60, 2937–2942. (c) Althius, T. H.; Kadin, S. B.; Czuba, L. J.; Moore,
P. F.; Hess, H. J. J. Med. Chem. 1980, 23, 262–269.
(17) Ranu, B. C.; Sarkar, A.; Guchhait, S. K.; Ghosh, K. J. Indian Chem.
Soc. 1998, 75, 690–694.
(18) For reduction of R,ꢀ-unsaturated nitroalkenes to aldoximes using tin
(II) chloride, see: Kabalka, G. W.; Goudgaon, N. M. Synth. Commun. 1988, 18,
693–697.
(19) Compagnone, R. S.; Suarez, A. I.; Zambrano, J. L.; Pina, I. C.;
Dominguez, J. N. Synth. Commun. 1997, 27, 1631–1641.
(20) Siegrist, U.; Baumeister, P.; Blaser, H.-U.; Studer, M.; The Selective
Hydrogenation of Functionalized Nitroarenes: New Catalytic Systems. In
Catalysis of Organic Reactions; Herkes, F. E., Ed. Marcel Dekker, Inc.: New
York, 1998; Vol 75, pp 207-219.
(21) Extension of the scope of this reductive cyclization to synthesize other
[3,2-c]-thienopyridines and various pyridine-containing heterocycles using both
the SnCl2 and Pt/V/H3PO2/H2 systems is currently under investigation and will
be reported in due course.
3852 J. Org. Chem. Vol. 74, No. 10, 2009

3-Substituted-4-amino-[3,2-c]-thienopyridines
washed once with 8% aqueous NaHCO3 (500 mL) and once with
25% aqueous NaCl (500 mL). The organic layer was concentrated
and chase-distilled twice with ethanol (400 mL portions). Ethanol
(400 mL) was added, the slurry was heated to reflux, and water
(400 mL) was added. The slurry was cooled to 0 °C and filtered.
The wet cake was washed once with water (100 mL) and the solids
were dried at 50 °C and 20 in. Hg to afford 4 (38.2 g, 93%) as an
off-white crystalline solid. Mp 161-163 °C; 1H NMR (400 MHz,
(CD3)SO) δ: 8.28 (d, J ) 5.4 Hz, 1H), 8.20 (d, J ) 5.4 Hz, 1H),
8.19 (s, 1H) ppm. 13C NMR (100 MHz, (CD3)SO) δ: 148.8, 143.3,
141.9, 129.4, 128.3, 181.1, 103.3 ppm. HRMS (ESI) for
C7H4BrClNS (M + H+) calcd 247.89309 found 247.89344.
3-Bromo-4-amino-[3,2-c]-thienopyridine (5). To a stainless
steel reactor was added 4 (403 g, 1.62 mol) followed by p-dioxane
(2.8 L) and 28% aqueous ammonia (2.8 L). The mixture was heated
to 150 °C and developed about 300 psi of pressure. After 19 h, the
reaction was cooled to 23 °C and filtered. The wet cake was washed
with water (800 mL) and dried at 23 °C and 20 in. Hg to afford 5
(235 g of 95 wt% purity, 61%) as a tan crystalline solid. A second
crop of crystals was isolated from the filtrate by heating to 50 °C
and adding water (6.1 L). The resulting slurry was cooled to 17 °C
and filtered. The wet cake was washed with water (930 mL) and
dried at 23 °C and 20 in. Hg to afford 5 (128 g of 87 wt% purity,
acetate (300 mL), heated to 55 °C, and then cooled to room
temperature. Heptane (600 mL) was added dropwise and the
resulting slurry stirred at ambient temperature for 16 h. The slurry
was filtered and the wet cake was washed with the crystallization
liquors. The product was dried at 50 °C and 20 in Hg overnight to
afford 10 (189.70 g, 82%) as a light-yellow crystalline solid. Mp
94-95 °C; 1H NMR (400 MHz, (CD3)SO) δ: 8.36 (t, J ) 5.8 Hz,
1H), 7.91 (d, J ) 3.3 Hz, 1H), 7.69 (d, J ) 3.3 Hz, 1H), 4.47 (t,
J ) 5.6 Hz, 1H), 3.29 (t, J ) 5.7 Hz, 2H), 3.28 (s, 6H) ppm. 13C
NMR (100 MHz, (CD3)SO) δ: 161.9, 135.7, 128.6, 125.2, 108.2,
101.5, 53.3, 40.9 ppm. HRMS (ESI) for C9H13BrNO3S (M + H+)
calcd 293.97940 found 293.97975.
3-Bromo-thieno[3,2-c]pyridin-4-ol (3) by Polyphosphoric
Acid Procedure. To a 12 L round-bottom flask was charged
polyphosphoric acid (3.3 kg, 105% grade) and 10 (250 g, 850
mmol). The reaction was heated to 100 °C. After 4 h the reaction
was cooled to 40 °C and water (6.6 L) was added over 15 min.
The slurry was cooled to 23 °C and filtered. The wet cake was
washed once with water (250 mL) and once with MeCN (250 mL).
The wet cake was dried at 45 °C and 20 in. Hg to afford 3 (193 g,
75.3 weight % purity as determined by HPLC assay using an
analytically pure standard, 98.5 peak area % purity by HPLC, 74%
purity adjusted yield) as a light-brown crystalline solid.
1
25%) as a tan crystalline solid. Mp 157-160 °C; H NMR (400
4-Bromothiophene-3-carboxamide (12). To a 500 mL round-
bottom flask was charged 9 (19.51 g, 94.22 mmol, 1.00 equiv)
followed by THF (195 mL). The solution was cooled to 10 °C and
SOCl2 (13.75 mL, 188.5 mmol, 2.00 equiv) was added at such a
rate as to keep the internal temperature below 25 °C. DMF (0.95
mL, 12 mmol, 0.13 equiv) was added and the reaction stirred at 23
°C for 3 h. To a separate 500 mL round-bottom flask was added
28% aqueous ammonia (85 mL) and the solution cooled to -10
°C. The acid chloride solution was added to the ammonia solution
at such a rate as to keep the internal temperature below 30 °C.
After one hour, the reaction reached 95% conversion as determined
by HPLC analysis. The reaction was diluted with EtOAc (100 mL)
and water (100 mL). The layers were separated and the aqueous
layer was extracted three times with EtOAc (100 mL each). The
combined organics were washed with brine (200 mL). The organics
were dried with MgSO4, filtered, and concentrated. To the resulting
white solid was added EtOAc (100 mL) and the slurry was heated
to 75 °C to dissolve all solids. Heptane (300 mL) was added and
the resulting slurry was cooled to 0 °C before filtration. The wet
cake was washed with heptane (50 mL) and dried at 50 °C and 20
in. Hg to afford 12 (13.74 g, 71%) as a white crystalline solid: 1H
NMR (400 MHz, (CD3)SO) δ: 7.97 (d, J ) 3.4 Hz, 1H), 7.72 (br
s, 1H), 7.68 (d, J ) 3.3 Hz, 1H), 7.36 (br s, 1H) ppm. 13C NMR
(100 MHz, (CD3)SO) δ: 163.2, 135.7, 128.6, 125.1, 108.3 ppm.
Anal. Calcd for C5H4BrNOS: C, 29.14; H, 1.96; Br, 38.78; N, 6.80;
O, 7.76; S, 15.56. Found: C, 29.17; H, 1.98; Br, 39.07; N, 6.70; S,
15.21.
4-Bromothiophene-3-carbonitrile (13). To a 250 mL round-
bottom flask was charged DMF (36 mL). The solution was cooled
to -10 °C and SOCl2 (13.9 mL, 117 mmol, 2.01 equiv) was added
at such a rate as to keep the internal temperature below 5 °C. The
reaction was cooled to -10 °C. After stirring for 20 min, 12 (12.00
g, 58.23 mmol, 1.00 equiv) was added at such a rate as to keep the
internal temperature below 10 °C. The reaction was cooled to -10
°C. After 90 min the reaction was warmed to 23 °C. After an
additional 3 h the reaction mixture was added to water (192 mL)
cooled to 5 °C. The reaction flask was rinsed once with DMF (12
mL). The slurry was cooled to 0 °C and filtered. The wet cake was
washed with water (36 mL) and dried at 50 °C and 20 in. Hg to
afford 13 (9.64 g, 87%) as a white crystalline solid: 1H NMR (400
MHz, (CD3)SO) δ: 8.70 (d, J ) 3.1 Hz, 1H), 7.98 (d, J ) 3.1 Hz,
1H) ppm. 13C NMR (100 MHz, (CD3)SO) δ: 139.4, 126.5, 113.5,
112.0, 110.1 ppm. Anal. Calcd for C5H2BrNS: C, 31.94; H, 1.07;
Br, 42.49; N, 7.45; S, 17.05. Found: C, 32.00; H, 1.06; N, 7.14;
Br, 42.77; S, 16.89.
MHz, (CD3)SO) δ: 7.81 (d, J ) 5.7 Hz, 1H), 7.74 (s, 1H), 7.25 (d,
J ) 5.7 Hz, 1H), 6.45 (br s, 2H) ppm. 13C NMR (100 MHz,
(CD3)SO) δ: 153.6, 147.2, 142.2, 122.4, 116.7, 107.5, 103.0 ppm.
HRMS (ESI) for C7H6BrN2S (M + H+) calcd 228.94296 found
228.94338.
t-Butyl-4-(4-aminothieno[3,2-c]pyridine-3-yl)phenylcarbam-
ate (6). To a 25 mL round-bottom flask was charged 5 (200 mg,
0.873 mmol, 1.00 equiv), t-butyl-4-(4,4,5,5,-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenylcarbamate (307 mg, 0.960 mmol, 1.10
equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
(35.6 mg, 0.0436 mmol, 0.05 equiv), and sodium carbonate (185
mg, 1.75 mmol, 2.0 equiv) followed by toluene (1 mL), ethanol (1
mL), and water (1 mL). The reaction was heated to 60 °C for 4 h,
at which point more toluene (2 mL), ethanol (2 mL), and water (2
mL) were added. The reaction was heated at 60 °C for an additional
16 h, at which point greater than 99% conversion of 5 was achieved
as determined by HPLC analysis. Water (10 mL) and ethyl acetate
(10 mL) were added and the layers were separated. The organic
layer was washed with brine, concentrated, and the residue purified
by silica gel chromatography (1% Et3N in hexanes grading in 15%
steps to 1% Et3N and 60% EtOAc in hexanes) to afford 6 (261
1
mg, 87%) as a tan crystalline solid. Mp 171-173 °C; H NMR
(400 MHz, (CD3)SO) δ: 9.54 (br s, 1H), 7.80 (d, J ) 5.7 Hz, 1H),
7.57 (m, 2H), 7.38 (s, 1H), 7.32 (m, 2H), 7.23 (d, J ) 5.7 Hz, 1H),
5.37 (br s, 2H), 1.49 (s, 9H) ppm. 13C NMR (100 MHz, (CD3)SO)
δ: 153.9, 152.1, 147.6, 141.2, 139.0, 136.0, 129.1, 122.1, 118.1,
117.5, 107.3, 79.1, 28.2 ppm. HRMS (ESI) for C18H20N3O2S (M
+ H+) calcd 342.12707 found 342.12866.
4-Bromo-thiophene-3-carboxylic Acid (2,2-Dimethoxy-ethyl)-
amide (10). To a 2 L round-bottom flask was added 9 (155 g, 738.4
mmol, 1.0 equiv) and thionyl chloride (379 mL, 7.384 mol, 10
equiv). Isopropyl acetate (775 mL) was added and the mixture was
heated at 50 °C until the carboxylic acid was consumed (18 h).
The reaction mixture was cooled to room temperature and chase-
distilled twice with isopropyl acetate (775 mL each). Isopropyl
acetate (775 mL) was added and the solution cooled to 10 °C. N,N-
diisopropylethylamine (319 mL, 1.846 mol, 2.5 equiv) was added
followed by aminoacetaldehyde dimethyl acetal (119.7 mL, 1.108
mol, 1.5 equiv). The reaction was exothermic. The reaction was
stirred at ambient temperature for 1 h and extracted with 10%
aqueous phosphoric acid (860 mL). The aqueous layer was extracted
with isopropyl acetate (300 mL) and the combined organic extracts
washed with 10% potassium dihydrogen phosphate (300 mL) and
water (150 mL). The organic layer was concentrated to a thick oil
that may crystallize. The crude product was dissolved in isopropyl
J. Org. Chem. Vol. 74, No. 10, 2009 3853

Engstrom et al.
t-Butyl-4-(4-cyanothiophen-3-yl)phenylcarbamate (14). To a
500 mL round-bottom flask was charged 13 (13.49 g, 71.7 mmol,
1.00 equiv), t-butyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenylcarbamate (25.18 g, 78.9 mmol, 1.10 equiv), [1,1′-
bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.76 g,
2.15 mmol, 0.03 equiv), and sodium carbonate (15.20 g, 143 mmol,
2.0 equiv) followed by PhMe, EtOH, and H2O (67.5 mL each).
The mixture was heated to 60 °C for 20 h, at which point greater
than 99% conversion of 13 was achieved as determined by HPLC
analysis. EtOAc (100 mL) and H2O (70 mL) were added. The
mixture was filtered and the wet cake washed once with 1/1 EtOAc/
brine (150 mL). The filtrate and wash were transferred to a
separatory funnel and the layers separated. The organic layer was
washed once with brine (150 mL). To the organic layer was added
Na2SO4 (26 g) and charcoal (6.5 g). The suspension was stirred
for 30 min and filtered through Celite (26 g). The filtrate was
concentrated and the residue purified by silica gel chromatography
(hexanes grading in 10% steps to 40% EtOAc in hexanes). The
product fractions were pooled and concentrated. The solids were
slurried in CH2Cl2 (40 mL) at 45 °C for 30 min and hexanes (160
mL) were added. The slurry was cooled to -4 °C, filtered, and the
wet cake washed once with hexanes (40 mL). The wet cake was
dried at 50 °C and 20 in. Hg to afford 14 (17.36 g, 80%) as a tan
crystalline solid. Mp 132-134 °C; 1H NMR (400 MHz, (CD3)SO)
δ: 9.51 (br s, 1H), 8.65 (d, J ) 3.2 Hz, 1H), 7.81 (d, J ) 3.1 Hz,
1H), 7.52 (m, 4H), 1.48 (s, 9H) ppm. 13C NMR (100 MHz,
(CD3)SO) δ: 152.1, 141.4, 139.2, 138.9, 127.4, 126.2, 123.7, 117.7,
115.2, 108.5, 79.1, 28.2 ppm. HRMS (ESI) for C16H17N2O2S (M
+ H+) calcd 301.10052 found 301.10129.
t-Butyl-4-(4-cyano-5-formylthiophen-3-yl)phenylcarbamate (15).
To a 250 mL round-bottom flask was charged 14 (3.20 g, 10.7
mmol, 1.0 equiv) followed by THF (64 mL). The solution was
cooled to - 5 °C and LDA (13.3 mL of 2.0 M in heptane/THF,
26.6 mmol, 2.5 equiv) was added at such a rate to keep the internal
temperature below 5 °C. After one hour, DMF (16 mL) was added
and the reaction was warmed to room temperature. After 30 min,
the reaction was greater than 99% conversion as determined by
HPLC analysis. Aqueous hydrochloric acid (96 mL of 1.0 M) was
added followed by EtOAc (64 mL). The layers were separated and
the organic layer was washed with aqueous hydrochloric acid (64
mL of 1.0 M), saturated aqueous NaHCO3 (64 mL), and brine (64
mL). The organic layer was concentrated and the residue purified
by silica gel chromatography (hexanes grading in 5% steps to 50%
EtOAc in hexanes). The product fractions were pooled and
concentrated. The solids were dissolved in CH2Cl2 (15 mL) at 45
°C. Hexanes (45 mL) were added and the resulting slurry was
cooled to 0 °C before filtration. The wet cake was washed twice
with hexanes (15 mL) and dried at 50 °C and 20 in. Hg to afford
15 (2.99 g, 85%) as a yellow crystalline solid. Mp 166-168 °C;
1H NMR (400 MHz, (CD3)SO) δ: 10.01 (d, J ) 1.1 Hz, 1H), 9.57
(br s, 1H), 8.31 (d, J ) 1.1 Hz, 1H), 7.57 (m, 4H), 1.49 (s, 9H)
ppm. 13C NMR (100 MHz, (CD3)SO) δ: 181.2, 152.0, 149.1, 143.8,
139.8, 131.4, 127.8, 125.0, 117.8, 113.2, 112.9, 79.2, 28.1 ppm.
HRMS (ESI) for C17H16N2O3SNa (M + Na+) calcd 351.07738
found 351.07717.
(CD3)SO) δ:152.0, 143.0, 142.2, 139.8, 138.7, 128.8, 127.6, 127.5,
125.2, 117.8, 113.9, 112.8, 79.2, 28.1 ppm. HRMS (ESI) for
C18H17N3O4SNa (M + Na+) calcd 394.08320 found 394.08269.
t-Butyl-4-(4-aminothieno[3,2-c]pyridine-3-yl)phenylcarbam-
ate (6) using SnCl2 Reduction. To a 50 mL round-bottom flask
was added 16 (2.00 g, 5.38 mmol, 1.0 equiv) followed by EtOAc
(10 mL) and SnCl2 ·2H2O (2.79 g, 12.4 mmol, 2.3 equiv). After
16 h, the reaction showed greater than 98% conversion as
determined by HPLC analysis. MeOH (10 mL) was added, the
reaction concentrated and chase distilled once from MeOH (20 mL).
The resulting oil was dissolved in MeOH (10 mL) and aqueous
K2CO3 (30 mL of a 10 wt% solution) was added. The resulting
slurry was stirred for 2 h. The slurry was filtered and the wet cake
washed once with H2O (10 mL). The combined filtrate and wash
contained 1.1% 17 as determined by HPLC analysis (for isolation
and characterization of 17, see the end of this experiment). The
wet cake was slurried in MeOH (20 mL) for 30 min, filtered, and
washed once with MeOH (10 mL). This wet cake reslurry proce-
dure was repeated two more times. The combined filtrate and
washes were filtered and the resulting MeOH solution contained
84.9% 17 as determined by HPLC analysis. (A pure standard of
17 was obtained by concentration of the MeOH solution and
purification of the residue by silica gel chromatography (CH2Cl2
followed by 10% MeOH in CH2Cl2) to afford 17 as a tan crystalline
solid. Mp 217-218 °C; 1H NMR (400 MHz, (CD3)SO) δ: 9.58 (br
s, 1H), 8.02 (d, J ) 7.0 Hz, 1H), 7.59 (m, 3H), 7.35 (m, 3H), 6.05
(br s, 2H), 1.49 (s, 9H) ppm. (400 MHz, (CD3OD) δ: 7.94 (dd, J
) 7.2, 0.5 Hz, 1H), 7.58 (m, 2H), 7.52 (d, J ) 0.4 Hz, 1H), 7.38
(m, 2H), 7.34 (d, J ) 7.1 Hz, 1H), 1.53 (s, 9H) ppm. 13C NMR
(100 MHz, (CD3)SO), δ:152.1, 145.4, 139.3, 137.5, 135.5, 132.5,
129.1, 127.7, 126.4, 119.3, 117.6, 106.7, 79.1, 28.2 ppm. HRMS
(ESI) for C18H20N3O3S (M + H+) calcd 358.12199 found 358.12316.)
The solution was concentrated and the resulting solids chase distilled
twice from EtOH (50 mL portions). The hazy solution was filtered
and the wet cake washed twice with EtOH (20 mL). The combined
filtrate and wash was concentrated and the resulting solids were
dissolved in EtOH (28 mL). To a pressure bottle was added 10%
Pd on carbon (150 mg) followed by EtOH (2 mL), AcOH (162
mg, 2.69 mmol, 0.5 equiv), and the EtOH solution of 17. The
mixture was put under a hydrogen atmosphere and heated to 70
°C. After 24 h, the reaction was greater than 99% conversion as
determined by HPLC analysis. The reaction was filtered through a
0.2 µm Teflon filter and the wet cake washed three times with EtOH
(10 mL). The combined filtrate and wash contained 84.6% 6 as
determined by HPLC analysis. The solution was concentrated and
chase distilled twice from EtOAc (30 mL portions). The resulting
solids were dissolved in EtOAc (40 mL). The organic solution was
washed once with saturated NaHCO3 (30 mL) and once with H2O
(30 mL). The organic layer was concentrated and chase distilled
twice from iPAc (30 mL portions). The resulting solids were slurried
in iPAc (10 mL) and heated to 80 °C. The solution was cooled to
ambient temperature and heptane (30 mL) was added. The slurry
was filtered and the wet cake washed once with heptane (10 mL).
The combined filtrate and wash contained 28.4% 6 as determined
by HPLC assay. The wet cake was dried at 50 °C and 20 in. Hg to
afford 6 (1.02 g, 55.6%) as a tan crystalline solid. The crystallization
was not optimized further. Spectral data matched that of material
synthesized by Suzuki cross-coupling of 5 and t-butyl-4-(4,4,5,5,-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (vide supra).
t-Butyl-4-(4-aminothieno[3,2-c]pyridine-3-yl)phenylcarbam-
ate (6) using Pt-V/C Reduction. To a 4 mL glass vial was added
3% Pt 0.6% V on carbon (9.5 mg dry basis) followed by water
(0.22 mL) and 50% aqueous hypophosphorous acid (0.14 mmol,
15 µL). After 15 min, the catalyst slurry was transferred to a 50
mL Hasteloy-C microreactor containing 16 (1.06 g, 2.86 mmol) in
THF (21 mL). The 4 mL vial was rinsed twice with water (0.10
mL portions). The reactor was pressurized to about 90 psig with
hydrogen gas and stirred at 95 °C for 10 h, during which time the
reaction reached greater than 99.9% conversion of 16 and 95%
(E)-t-Butyl-4-(4-cyano-5-(2-nitrovinyl)thiophen-3-yl)phenyl-
carbamate (16). To a 250 mL round-bottom flask was charged 15
(8.00 g, 24.4 mmol, 1.0 equiv) followed by MeCN (20 mL) and
CH3NO2 (20 mL). DMAP (298 mg, 2.44 mmol, 0.1 equiv) was
added and the reaction reached 98% conversion after 2 h as
determined by HPLC analysis. After another hour, MeCN (120 mL)
was added followed by Ac2O (3.73 g, 36.5 mmol, 1.5 equiv). After
15 min, the reaction reached greater than 99% conversion of the
intermediate alcohol as determined by HPLC analysis. The reaction
was cooled to -5 °C and filtered. The wet cake was washed once
with MeCN (40 mL) and dried at 50 °C and 20 in. Hg to afford 16
(8.27 g, 91%) as an orange crystalline solid. Mp 219-220 °C; 1H
NMR (400 MHz, (CD3)SO) δ: 9.56 (br s, 1H), 8.22 (ABq, 2H),
8.13 (s, 1H), 7.56 (m, 4H), 1.48 (s, 9H) ppm. 13C NMR (100 MHz,
3854 J. Org. Chem. Vol. 74, No. 10, 2009

3-Substituted-4-amino-[3,2-c]-thienopyridines
conversion of 17 as determined by HPLC analysis. The reaction
was cooled to ambient temperature, filtered through a 0.2 µm Teflon
filter, and rinsed with THF. The solvent was evaporated and EtOAc
(15 mL) was added. The organics were washed once with 50%
saturated aqueous NaHCO3 (10 mL) and twice with water (10 mL
portions). The solvent was evaporated and the residue purified by
silica gel chromatography (25% EtOAc in heptane grading to 100%
EtOAc). The product fractions were pooled and concentrated to
afford 6 (0.747 g, 77%) as a tan foam. Spectral data matched that
of material synthesized by Suzuki cross-coupling of 5 and t-butyl-
4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (vide
supra).
Acknowledgment. We would like to thank Bryan Macri and
Brian Kotecki of the Abbott Laboratories Catalysis Laboratory
for running high pressure reactions and initial screening of
reductive cyclization of 16 using hydrogen. We would like to
thank Dr. Ian Marsden for structural analysis of compound 16.
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra for compounds described in the experimental
section. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO9003772
J. Org. Chem. Vol. 74, No. 10, 2009 3855