Facile preparation of thiophene C2-ethers using the Mitsunobu reaction

Article abstract of DOI:10.1016/j.tetlet.2008.07.153

The preparation of thiophene ethers generally requires forcing conditions thus limiting the choice of alkyl substituent. Herein, we report the first successful generally applicable conditions for the selective O-alkylation of 2(5H)-thiophenone.

Full text of DOI:10.1016/j.tetlet.2008.07.153

Tetrahedron Letters 49 (2008) 5946–5949
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Tetrahedron Letters
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Facile preparation of thiophene C2-ethers using the Mitsunobu reaction
*
Craig S. Harris , Hervé Germain, Georges Pasquet
AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of thiophene ethers generally requires forcing conditions thus limiting the choice of alkyl
substituent. Herein, we report the first successful generally applicable conditions for the selective
O-alkylation of 2(5H)-thiophenone.
Received 2 July 2008
Revised 22 July 2008
Accepted 29 July 2008
Available online 31 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to the memory of the late Dr.
Patrice Siret whose vision and passion for
modern pharmaceutical research was an
inspiration for all
Keywords:
Thiophenone
Mitsunobu alklyation
During recent years, the pharmaceutical industry has been
investigating new approaches to treat cancer including inhibition
of cell-growth signalling pathways1 and anti-angiogenesis2 as well
as inhibition of DNA synthesis and function.3 We became
interested in targeting thiophene ethers at C-2 having the
bidentate binding bases, 2-amino-6-methylpyridine4 and tetra-
hydronaphthyridine (Fig. 1).5
There are 2 logical possible retrosyntheses of key substructure
1; using Ullman-style chemistry6 from either the corresponding
2-bromo- or 2-iodothiophene precursors and the appropriate alco-
hol; or alkylation from commercially available 2(5H)-thiophenone
with the appropriately functionalised side chain.7
6-picoline.4 Boc protection followed by alkylation with iodometh-
ane afforded 3. Lithiation followed by carbonylation and reduction
of the ethyl ester afforded 4 in acceptable overall yields. The
synthesis of
7 relied upon a smooth cyclocondensation of
2-amino-3-formylpyridine with acetone in the presence of
L
-proline to afford the naphthyridine intermediate which was in
turn reduced (Pd–C/EtOH) and N-protected with a Boc group.5
The intermediate 6 was subjected to similar chemistry as used
for the preparation of 4 to afford 7 in good overall yield (Scheme 1).
The general method to synthesise thiophene ethers at the
a
position is to use Ullman-style approaches.6 However, all attempts
to apply Ullman-style approaches,7 including recent milder condi-
tions,8 even from aryltrifluoroborate precursors,9 and palladium-
catalysed alternatives10 only afforded traces of product. The
The side chains were prepared by adapting existing literature.
The synthesis of 4 started from commercially available 2-amino-
N
N
H
a
HO
Br/I
O
S
S
N
b
a
N
H
O
S
b
N
H
Substructure of interest (1)
N
LG
Figure 1. Synthons which could give the desired substructure.
* Corresponding author. Tel.: +33 03 26 61 5912; fax: +33 03 26 61 6842.
E-mail address: craig.harris2@astrazeneca.com (C. S. Harris).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.153

C. S. Harris et al. / Tetrahedron Letters 49 (2008) 5946–5949
5947
(i)
O
(iii)
(iv)
O
(ii)
H2N
N
O
N
N
O
N
N
OH
2
3
4
O
(v)
(viii)
(ix)
(vi)
H2N
N
N
N
OH
N
N
(vii)
O
O
O
O
7
5
6
Scheme 1. Synthesis of key side chains 4 and 7. Reagents and conditions: (i) Boc–O–Boc, THF, 60 °C, 66%; (ii) Me–I, NaH, DMSO, 82%; (iii) LDA, EtO(CO)OEt, À78 °C to rt, 4 h,
51%; (iv) LiBH4, THF, À10 °C to rt, 95%; (v) -proline, acetone, EtOH, reflux, 16 h, 74%; (vi) H2, Pd–C, EtOH, rt, 95%; (vii) Boc–O–Boc, LiHDMS, THF, À78 °C to rt, 50%; (viii)
LiHDMS, EtO(CO)OEt, À78 °C to rt, 4 h, 78% and (ix) LiBH4, THF, À10 °C to rt, 75%.
L
pyridine ethanol-based side chains readily eliminate at moderate
to high temperatures under basic conditions to afford the corre-
sponding vinyl pyridine side products, and we could not overcome
this by modifying the conditions (ligand, temperature, copper
source, etc.).
X
R
+
R
O
O
S
S
2(5
H
)-thiophenone
pKa 10.63
Consequently, we turned our attention to the alkylation of
2(5H)-thiophenone (Scheme 2). From the few relevant references
Scheme 2. Alkylation of thiophenone.
Table 1
Selected results from the Mitsunobu alkylation of 2(5H)-thiophenone by RX15
Entry
R
X
Alkylation conditions
Isolated yield (%)
—
O
O
O
1
Cl/OMs
Classical: NaH or K2CO3, THF or DMF, rt to 80 °C
N
N
N
N
N
N
O
O
O
2
3
OH
OH
DTAD added at the end to a stirred mixture of
2(5H)-thiophenone, PS–TPP and alcohol at À10 °C to rt
—
A: 2(5H)-thiophenone added to a suspension ofPS–TPP–O–R
(preformed by adding alcohol to the PS–betaine intermediate)
49
4
5
OH
OH
A
A
51
15
N
N
O
O
N
N
N
N
6
7
8
9
OH
OH
OH
OH
B: solution of 2(5H)-thiophenone and alcohol added
to a stirred solution of betaine
53
94
83
CH3
A
B
A
O
66
N
(continued on next page)

5948
C. S. Harris et al. / Tetrahedron Letters 49 (2008) 5946–5949
Table 1 (continued)
Entry
R
X
Alkylation conditions
Isolated yield (%)
69
O
10
OH
A
N
O
11
12
OH
OH
A
A
66
78
N
N
O
N
13
14
OH
OH
B
B
58
64
15
16
OH
OH
B
B
49
41
O
O
N
O
O
on this alkylation,7,11,12 one can quickly establish that this is not
generally seen as a preparatively useful way into ethers at the
ate the 2(5H)-thiophenone with the mesylate or chloride of 4 affor-
ded the vinylpyridine by-product and traces of product (entry 1).
The mode of addition of the Mitsunobu reagents had a critical
bearing on the actual yields (entry 2 vs entry 3), whereby the DTAD
needed to be consumed before adding the reactive 2(5H)-thiophe-
none (alkylation conditions A). Moreover, in the case of tetra-
hydronaphthyridine with no N-Boc protection, it was essential to
add the alcohol and 2(5H)-thiophenone at the same time to the
betaine intermediate in order to reduce elimination and maximise
yields (entry 5 vs entry 6, alkylation conditions B). Alcohols con-
taining basic functionality (e.g., entries 9 and 13), secondary alco-
hols (e.g., entries 8, 11, 13, and 16), alcohols serving as protecting
groups (e.g., entry 15) and elimination-prone chiral alcohols (e.g.,
entry 16) can all be transformed in acceptable to excellent overall
yields with this process. During the course of the alkylation, C3-
alkylation is occasionally observed by LCMS but at unsignificant
levels (<5%).
a-
position of thiophene. All the references cited classical alkylation
conditions (alkyl halides in the presence of a mineral base) with
low yields and C-alkylation at C-3 posing the most serious prob-
lems. However, all attempts to apply the most appealing condi-
tions (NaH, mesylate and THF)7 to our case resulted only in
elimination, affording, as in the Ullman trials, the vinylpyridine
as the majority product. Even when the reaction was carried out
with phenol, elimination dominated with little product observed
confirming that classical alkylation methods were not applicable
to our particular side chains.
The pKa of 2(5H)-thiophenone was measured at 10.63,13 sug-
gesting it could be a suitable substrate for milder, more tolerant
Mitsunobu alkylation conditions,14 well documented for favouring
substitution over elimination. However, to our knowledge there is
no reference identifying the Mitsunobu reaction as a suitable an-
swer to this particular problem, although the process is generally
used for alkylations with 4 and 7 of phenolic substrates.4,5 After
a significant amount of process development, we managed to suc-
cessfully apply Mitsunobu conditions to this sensitive alkylation.
The mode of addition of the Mitsunobu reagents was absolutely
critical. If the di-tert-butylazodicarboxylate (DTAD) was not pre-re-
acted with triphenylphosphine (TPP) to form the betaine interme-
diate before 2(5H)-thiophenone was introduced, the reaction failed
resulting in electrophilic substitution at C-3 by DTAD. The best
conditions for readily eliminable side chains involved adding a
solution of the alcohol and 2(5H)-thiophenone in dichloromethane
to a stirred solution of the betaine (pre-formed by adding DTAD to
TPP at À10 °C over a period of 5 min) at À10 °C (acetone/ice).
With the conditions optimised, we decided to apply these to a
broader range of alcohols. Table 1 shows the results obtained from
a selection of alcohols. As mentioned previously, attempts to alkyl-
In conclusion, we have discovered a new application of the
Mitsunobu reaction that allows access to acceptable yields of a di-
verse set of thiophene ethers at C-2 otherwise difficult to attain
using existing methodology.
Acknowledgement
The authors would like to acknowledge Dr. Gilles Ouvry, Dr. J.-C.
Arnould, Dr. Bernard Barlaam, Dr. Bénédicte Delouvrie, Mr. Jacques
Pelleter and Dr. Delphine Dorison-Duval for their interest and
analytical support.
References and notes
1. Ding, J.; Feng, Y.; Wang, H.-Y. Acta Pharm. Sin. 2007, 9, 1494–1498.
2. Kerbel, R.; Folkman, J. Nat. Rev. Cancer 2002, 2, 727–739.
3. Teicher, B. A. Clin. Cancer Res. 2008, 14, 1610–1617.

C. S. Harris et al. / Tetrahedron Letters 49 (2008) 5946–5949
5949
4. (a) Li, L.-S.; Rader, C.; Matsushita, M.; Das, S.; Barbas, C. F., III; Lerner, R. A.;
Sinha, C. S. J. Med. Chem. 2004, 47, 5630–5640; (b) Miller, W. H.; Gleason, J. G.;
Heerding, D.; Samanen, J. M.; Uzinskas, I. N.; Manley, P. J. PCT Int. Appl. WO99/
45972.
5. Penning, T. D.; Penning, T. D.; Khilevich, A.; Chen, B. B.; Russell, M. A.; Boys, M.
L.; Wang, Y.; Duffin, T.; Engleman, V. W.; Finn, M. B.; Freeman, S. K.; Hanneke,
M. L.; Keene, J. L.; Klover, J. A.; Nickols, G. A.; Nickols, M. A.; Rader, R. K.; Settle,
S. L.; Shannon, K. E.; Steininger, C. N.; Westlin, M. M.; Westlin, W. F. Bioorg. Med.
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Chem. Ges. 1904, 37, 853–854; (c) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39,
1691–1692. for an excellent review see a recent article from (d) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
7. Alkylation of 2(5H)-thiophenone with the bis(mesylate) of hexan-diol:
Jew, S.-s.; Kim, E.-k.; Je, S.-m.; Zhao, L.-X.; Kim, H.-o.; Park, H.-g.; Ko, K.-h.;
Kim, W.-k.; Kim, H.-J.; Cheong, J. H.; Lee, E.-S. Heterocycles 2000, 52, 1087–1104.
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3490–3491.
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13. The pKa of 2(5H)-thiophenone was determined by multi-wavelength
spectrophotometry on a Sirius GlpKa, sweeping the pH from 2.5 to 11.5 and
returning to 2.5. The analyte, composed of 2 mg of substrate, was dissolved in
200 ll of DMSO; 7.5 ll of this solution was diluted with 250 ll of a buffer
solution containing 0.2 g of KH2PO4 dissolved in 100 ml of water.
14. Mitsunobu, O. Synthesis 1981, 1–28.
15. Typical procedure A: To a stirred solution/suspension of triphenylphosphine/
polymer-supported triphenylphosphine (3 equiv, 1.6 mmol/g) was added di-
tert-butyl azodicarboxylate (DTAD, 3 equiv) in dichloromethane (5 ml/ 100 mg
of input thiophenone) at À10 °C. The solution was stirred for 10 min at À10 °C
and a solution of the alcohol (3 equiv) in dichloromethane (1 ml) was added.
The resulting suspension was slowly agitated for 20 min and 2(5H)-
thiophenone (1 equiv)* in dichloromethane (1 ml) was added dropwise to
the mixture over a period of time so that the internal temperature did not rise
above 0 °C. After the addition was complete, the solution/suspension was
stirred at room temperature for 1 hour, filtered if necessary, concentrated to
dryness and the residue was generally purified by flash chromatography on
silica gel eluting with gradient of pentane/dichloromethane (100:0) to
dichloromethane/MeOH (90:10) to afford the title compounds generally as
oils. For non-polar ethers (e.g., entry 7), the reduced DTAD could be eliminated
by trituration with pentane prior to purification. *Procedure B involved the
simultaneous addition of the alcohol (3 equiv) and 2(5H)-thiophenone
(1 equiv) in dichloromethane (1 ml) to a stirred suspension of the betaine at
À10 °C.
9. Batey, R. A.; Quach, T. A. Org. Lett. 2003, 5, 1381–1384.
10. Humphries, P. S.; Bailey, S.; Do, Q. T.; Kellum, J. H.; McClellan, G. A.; Wilhite, D.
M. Tetrahedron Lett. 2006, 47, 5333–5336.
11. Some relevant references around the subject include: (a) Hinrichs, H.;
Margaretha, P. Chem. Ber. 1992, 125, 2311–2317; (b) Kiesewetter, R.;
Margaretha, P. Helv. Chim. Acta 1989, 72, 83–92.