Regio- and chemoselective synthesis of fully substituted thiophenes

Article abstract of DOI:10.1021/ol802513q

(Chemical Equation Presented) A full functionalization of all four positions of the thiophene ring was achieved. Starting from readily available 2,5-dichlorothiophene, successive magnesiations of the 3- and 4-positions using TMPMgCl·LiCl furnish, after tr

Full text of DOI:10.1021/ol802513q

ORGANIC
LETTERS
2009
Vol. 11, No. 2
445-448
Regio- and Chemoselective Synthesis of
Fully Substituted Thiophenes
Fabian M. Piller and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received October 30, 2008
ABSTRACT
A full functionalization of all four positions of the thiophene ring was achieved. Starting from readily available 2,5-dichlorothiophene, successive
magnesiations of the 3- and 4-positions using TMPMgCl·LiCl furnish, after trapping with various electrophiles, 3,4-difunctionalized
dichlorothiophenes. Subsequent dechlorination and metalation or magnesium insertion into the C-Cl bond provides fully functionalized
thiophenes in high yields. An application to the synthesis of a thiophene analogue of Atorvastatin (Lipitor) is reported.
The thiophene moiety is an important building block for
various new materials1 and modern drug design.2 Five of
the 100 top selling drugs in the U.S. in 2007 included a
thiophene subunit.3 Directed lithiations are known for all
positions of the thiophene ring but often require low
temperatures and have a low tolerance toward functional
groups.4 Magnesiations using amide bases or magnesates are
compatible with some sensitive functionalities but can only
be performed at the activated 2- or 5-positions.5 Recently,
we have reported directed magnesiations of aromatic and
heteroaromatic substrates using the new mixed Mg/Li-amide
TMPMgCl·LiCl (1; TMP ) 2,2,6,6-tetramethylpiperidyl).6
Herein we report that by using this reagent, it is possible to
fully functionalize the thiophene ring starting from com-
mercially available 2,5-dichlorothiophene (2). Thus, the
thiophene 2 can be successively metalated at both the 3- and
4-position using TMPMgCl·LiCl (1) and leads, after quench-
ing with electrophiles, to substituted thiophenes of type 5.
The chlorine atoms at the 2- and 5-positions are excellent
directing groups for the metalations at the 3- and 4-positions.
After reductive cleavage of the C-Cl bonds, the intermediate
6 is then regioselectively deprotonated at the 2- and then
the 5-position again using TMPMgCl·LiCl (1), leading to
fully functionalized thiophenes of type 7 (Scheme 1).
(1) (a) Osaka, I.; McCullough, R. D. Acc. Chem. Res. 2008, 41, 1202.
(b) Perepichka, I. F.; Perepichka, D. F.; Meng, H.; Wudl, F. AdV. Mater.
2005, 17, 2281. (c) McCullough, R. D. AdV. Mater. 1998, 10, 93. (d)
Sebastian, M.; Hissler, M.; Fave, C.; Rault-Berthelot, J.; Odin, C.; Re´au,
R. Angew. Chem., Int. Ed. 2006, 45, 6152.
Thus, the reaction of 2,5-dichlorothiophene (2) with
TMPMgCl·LiCl (1; 1.1 equiv, 25 °C, 30 min) leads to the
corresponding 3-magnesiated thiophene 3, which can be
trapped with PhSO2SMe giving the thiomethylated compound
4a in 92% yield. The subsequent deprotonation of 4a using
TMPMgCl·LiCl (1) also proceeds smoothly (-10 °C, 30
(2) (a) Swanston, J. Thiophenes. In Ullmann’s Encyclopedia of Industrial
Chemistry; Wiley-VCH: Weinheim, 2006. (b) Sperry, J. B.; Wright, D. L.
Curr. Opin. Drug DiscoVery DeV. 2005, 8, 723. For recent examples see:
(c) Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; Cara, C. L.; Cruz-Lopez,
O.; Iaconinoto, M. A.; Preti, D.; Shryock, J. C.; Moorman, A. R.; Vincentzi,
F.; Varani, K.; Borea, P. A. J. Med. Chem. 2008, 51, 5875. (d) Aurelio, L.;
Figler, H.; Flynn, B. L.; Linden, J.; Scammells, P. J. Bioorg. Med. Chem.
2008, 16, 1319.
(3) Plavix , Cymbalta , Zyprexa , Spiriva and Evista : Lamb, E.
Pharm. Times 2008, (May), 20.
(4) (a) Carpenter, A. J.; Chadwick, D. J. J. Org. Chem. 1985, 50, 4362.
(b) Doat, E. G.; Snieckus, V. Tetrahedron Lett. 1985, 26, 1149.
(5) (a) Shilai, M.; Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans.
1 2001, 442. (b) Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Tre´court,
F.; Que´guiner, G.; Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros, R.
Tetrahedron 2005, 61, 4779.
(6) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.; Knochel, P. Org. Lett.
2006, 8, 5673. (c) Mosrin, M.; Knochel, P. Org. Lett. 2008, 10, 2497. (d)
Clososki, G.; Rohbogner, C. J.; Knochel, P. Angew. Chem., Int. Ed. 2007,
46, 7681. (e) Rohbogner, C. J.; Clososki, G.; Knochel, P. Angew. Chem.,
Int. Ed. 2008, 47, 1503.
10.1021/ol802513q CCC: $40.75
Published on Web 12/17/2008
2009 American Chemical Society

Scheme 1
.
Reaction Sequence Starting from
Table 1. Synthesis of 3,4-Disubstituted Thiophenes of Type 5
2,5-Dichlorothiophene (2) for the Synthesis of Fully
Functionalized Thiophenes of Type 7
min), and the resulting magnesiated intermediate is reacted
with DMF, yielding the aldehyde 5a in 95% yield (Table 1,
entry 1).
Treatment of the magnesiated intermediate 3 with ethyl
cyanoformate yields the ester 4b7 in 76% yield. A subsequent
deprotonation of 4b7 proceeds smoothly (-30 °C, 30 min),
and the expected products 5b-d are isolated in 76-95%
yield after a Pd-catalyzed cross-coupling8 reaction, a reaction
with an acid cyanide,9 or a Cu(I)-catalyzed allylation10
(entries 2-4). Similarly, the 3-magnesiated thiophene 3
reacts directly with Boc2O affording the ester 4e7 in 82%
yield. Subsequent metalation and again trapping with Boc2O
furnishes the diester 5e in 79% yield (entry 5). Ketones are
sensitive functional groups and often react with polar
organometallics. However, the Cu(I)-catalyzed10 quenching
of the 3-thienylmagnesium reagent 3 with acid chlorides
affords the ketones 4f7 and 4g.7 These ketones readily
undergo metalation using 1 (-78 to -50 °C, 30 to 45 min),
and after Negishi cross-coupling8 reactions with 4-iodoben-
zonitrile or 4-chloroiodobenzene, the arylated products 5f
and 5g are obtained in 77-84% yield (entries 6 and 7).
Similarly, a cyano-function is tolerated as well. Thus, the
treatment of the magnesium reagent 3 with TsCN furnishes
the nitrile 4h7 in 73% yield. After a subsequent metalation
of 4h7 (-30 °C, 15 min) and trapping of the resulting
magnesium reagent with DMF, the functionalized aldehyde
5h is obtained in 86% yield (entry 8).
The synthesis of 3,4-substituted chlorothiophenes of type
5 is also possible using the crude intermediate products of
type 4. Thus, the reaction of the magnesium compound 3
with ethyl cyanoformate gives the corresponding 3-substi-
(7) All compounds are depicted in Supporting Information, and their
preparation is fully described.
(8) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Negishi, E Acc. Chem. Res. 1982, 15, 340. A
transmetalation from Mg to Zn proved to be convenient due to the higher
stability of Zn-reagents compared to the corresponding Mg-reagents.
(9) Duplais, C; Bures, F.; Sapountzis, I.; Korn, T. J.; Cahie´z, G.; Knochel,
P. Angew. Chem., Int. Ed. 2004, 43, 2968.
a Isolated yield of analytically pure product. b After transmetalation using
ZnCl2 (1.1 equiv) and a Pd-catalyzed cross-coupling reaction. c After
transmetalation using CuCN·2LiCl (20 mol %). d Overall yield over two
steps.
(10) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
446
Org. Lett., Vol. 11, No. 2, 2009

Scheme 2
.
Synthesis of Thiophenes of Type 6 using Pd/C and
HCO2NH4 under Microwave Irradiation
Scheme 3. Synthesis of Fully Substituted Thiophenes of Type 7
tuted dichlorothiophene. After an aqueous workup, the crude
mixture is again treated with TMPMgCl·LiCl (1; -30 °C,
30 min) and quenched with NCCO2Et, yielding the diester
5i in 87% overall yield (entry 9). Similarly, PhSO2SMe or
an acid chloride can be used as a second electrophile (E2)
leading to the 3,4-substituted thiophenes 5j and 5k in
67-73% overall yield (entries 10 and 11). When quenching
the thienylmagnesium reagent 3 with PhSO2SMe, the sub-
sequent deprotonation of the crude reaction mixture proceeds
smoothly (-10 °C, 30 min), and the resulting magnesium
reagent can be used in a Pd-catalyzed cross-coupling
reaction8 to give the expected product 5l in 84% overall yield
(entry 12).
The reductive cleavage of a carbon-chlorine bond can be
achieved by various metal-catalyzed reactions.11 We chose
the method developed by Schlosser using Pd/C and am-
monium formate as a reductive system.12 However, we have
observed that conventional heating leads to a sluggish
reaction. For example, the reduction of the dichlorothiophene
5g in EtOH at 80 °C using a sealed tube requires 5 days to
achieve completion. However, by using microwave irradia-
tion (100 W, 70 °C, open vessel), the reduction is complete
within 5 h and the dechlorinated thiophene 6a is isolated in
76% yield.
Remarkably, this reduction is completely selective and
only reduces the carbon-chlorine bonds at the thiophene
ring without affecting other aromatic C-Cl bonds (see
Scheme 2, compound 6a). The same procedure is used for
the chlorothiophenes 5f, 5j, and 5k (5-6 h, 100 W, 70 °C,
open vessel) furnishing the dechlorinated products 6b-d in
77-95% yield (Scheme 2).
A further deprotonation of the dechlorinated thiophenes
of type 6 is achieved with complete regioselectivity. When
treating the thiophene 6b and 6c with TMPMgCl·LiCl (1;
1.1 equiv, -40 to -30 °C, 30-60 min), the ester moiety is
acting as a directing group13 and magnesation occurs
regioselectively next to this ester group. Cu(I)-catalyzed
allylation10 or Pd-catalyzed cross-coupling reactions8 afford
the expected products 8a-8d in 57-93% yield. Similarly,
a ketone can also play the role of an efficient directing group,
and the product 8e is isolated in 92% yield after deproto-
nation of 6a and quenching with NCCO2Et.
The remaining 5-position can be metalated as well between
-50 and -20 °C with TMPMgCl·LiCl (1; 1.1 equiv, 30-45
min). The resulting magnesiated intermediates are trapped
with aldehydes and DMF or can be used in allylations10 or
cross-coupling reactions8 furnishing the fully substituted
thiophene derivatives 7a-7f in 70-87% yield. Moreover,
the magnesiated thiophene derived from thiophene 8b can
be subjected to a transition-metal-free homocoupling reaction
using chloranil,14 and the highly functionalized dithiophene
7g is obtained in 63% yield (Scheme 3).
Recently, we have reported a LiCl-mediated magnesium
insertion into aryl chlorides and bromides under mild and
convenient conditions.15By using this method, the dichlo-
rothiophenes of type 5 can also be magnesiated directly at
the 2- and 5-positions. Thus, the addition of the dichlo-
rothiophene 5j to Mg turnings (2.5 equiv), LiCl (1.25 equiv),
and ZnCl2 (1.1 equiv) in THF regioselectively gives the
zincated intermediate 9 (25 °C, 3 h), which can be arylated
in a Pd-catalyzed reaction with 4-iodoanisole leading to the
(13) (a) Macklin, T.; Snieckus, V. In Handbook of C-H Transforma-
tions; Dyker G., Ed.; Wiley-VCH: Weinheim, 2005; p 106. (b) Hartung,
C. G.; Snieckus V. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-
VCH: Weinheim, 2002; p 330.
(11) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2002, 102, 4009.
(12) (a) Marzi, E.; Bobbio, C.; Cottet, F.; Schlosser, M. Eur. J. Org.
Chem. 2005, 2116. (b) Bobbio, C.; Rausis, T.; Schlosser, M. Chem. Eur. J.
2005, 11, 1903.
(14) Krasovskiy, A.; Tishkov, A.; del Amo, V.; Mayr, H.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 5010.
(15) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.; Knochel,
P. Angew. Chem., Int. Ed. 2008, 47, 6802.
Org. Lett., Vol. 11, No. 2, 2009
447

Scheme 4
.
Magnesium Insertion into Dichlorothiophenes of
Scheme 5
.
Application to the Synthesis of a Thiophene-Based
Atorvastatin (Lipitor) Derivative
Type 5
arylated product 10 in 91% yield. Repeated treatment of 10
with Mg turnings, LiCl, and ZnCl2 (25 °C, 4 h) affords the
zinc compound 11, and following an allylation reaction
catalyzed by CuCN·2LiCl (20 mol %),10 the fully function-
alized thiophene 12 is isolated 71% yield (Scheme 4).
As an application, we have prepared a thiophene analogue
of Atorvastatin (13; Lipitor, HMG-CoA reductase inhibitor,
anticholesterol agent) starting from 2,5-dichlorothiophene
(2).16 Using the procedure described above, selective depro-
tonations and successive quenching with ethyl cyanoformate
and iodobenzene in a Negishi cross-coupling reaction
furnishes the 3,4-disubstituted dichlorothiophene 14 in 69%
yield. Regioselective magnesium insertion in the presence
of LiCl and ZnCl2 (25 °C, 3 h) and subsequent Pd-catalyzed
cross-coupling with 2-bromopropene (using Pd(OAc)2 and
SPhos17 as a catalytic system) affords the alkene 15 in 94%
yield. The Mg-insertion into the remaining C-Cl bond of
15 proceeds smoothly (25 °C, 3 h). A Negishi cross-coupling
reaction with 4-bromofluorobenzene then yields the arylated
product 16 in 66% yield. After hydrogenation of the double-
bond and amide formation using Weinreb’s method18 (Ph-
NH2, AlMe3), the thiophene analogue 17 of Atorvastatin (13)
is obtained in 85% yield (36% overall yield, Scheme 5).
In summary, we have reported a complete functionalization
of all positions of the thiophene ring starting from readily
available 2,5-dichlorothiophene (2) using the powerful base
TMPMgCl·LiCl (1).19 This method is tolerating important
functional groups, such as ketones, esters or nitriles. Exten-
sions of this reaction to other heterocyclic systems is
currently underway in our laboratories.
Acknowledgment. We thank the European Research
Council (ERC), the Deutsche Forschungsgemeinschaft (DFG),
SFB 749, and the Fonds der Chemischen Industrie for
financial support. We thank W. C. Heraeus GmbH (Hanau),
Chemetall GmbH (Frankfurt), BASF AG (Ludwigshafen),
and Evonik Industries AG (Hanau) for the generous gift of
chemicals.
Supporting Information Available: Experimental pro-
cedures and full characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Similar structures have been reported as steroid nuclear receptor
modulators and protein kinase inhibitors: (a) Flatt. B.; Gu, X. H.; Martin,
R.; Mohan, R.; Murphy, B.; Nyman, M.; Stevens, W. C.; Wang, T. L.;
Bannen, L. C. Patent WO 2007024744, 2007. (b) Brenchley, G.; Charrier,
J.-D.; Durrant, S.; Knetgel, R; Ramaya, S. Patent WO 2007139816, 2007.
(17) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 468.
OL802513Q
(18) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
48, 4171.
(19) TMPMgCl·LiCl (1) is available from Chemetall (Frankfurt) and
Aldrich.
448
Org. Lett., Vol. 11, No. 2, 2009