Preparations and reactions of SF5-substituted aryl and heteroaryl derivatives via Mg and Zn organometallics

Article abstract of DOI:10.1002/chem.201201485

Polyfunctional SF₅-substituted cycles: Several organometallic sequences using zinc, copper, and magnesium intermediates were developed to prepare a broad range of SF₅-substituted aromatic and heterocyclic compounds of potential interest for pharmaceutical applications. Copyright

Full text of DOI:10.1002/chem.201201485

COMMUNICATION
DOI: 10.1002/chem.201201485
Preparations and Reactions of SF5-Substituted Aryl and Heteroaryl
Derivatives via Mg and Zn Organometallics
Annette Frischmuth,[a] Andreas Unsinn,[a] Klaus Groll,[a] Heinz Stadtmꢀller,[b] and
Paul Knochel*[a]
The physico-chemical and pharmacological properties of
organic molecules are often significantly modified by the in-
corporation of fluorine atoms.[1] The preparation of fluoro-
or trifluoromethyl-substituted aromatics and hetero-
ganometallic transformations that allow the preparation of
various SF5-substituted aromatics and heteroaromatics.
We initially investigated the Br/Mg exchange to prepare
SF5-substituted magnesium intermediates (Table 1). The
commercial SF5-substituted aryl bromide 1 furnished, after
treatment with iPrMgCl·LiCl (1.1 equiv), the arylmagnesium
halide 2 within 1 h at 08C in 80% yield.[13] This magnesium
reagent 2 reacted with various electrophiles in good yields.
Thus, after a transmetalation with ZnCl2, a Pd-catalyzed
cross-coupling with 4-bromobenzonitrile (3a) or 5-bromo-
ACHTUNGTRENNUNG
aromatics has become an active research field.[2] Recently, it
has been shown that the replacement of CF3 groups with
SF5 substituents may increase the biological activity of phar-
macologically active substances.[3] Also, due to its specific
physico-chemical properties[4] and to the increased availabil-
ity of SF5-substituted starting materials,[5] this fluorous group
is beginning to find many applications in material scien-
ces.[3,6] However, synthetic methods leading to SF5-substitut-
ed aryl and heteroaryl derivatives are rare.[3]
AHCTUNGTRENNUNG
picolinonitrile (3b) (2% PEPPSI-iPr[14]) furnished the func-
tionalized SF5-substituted biphenyls 4a and 4b in 83–79%
yield (Table 1, entries 1 and 2). Remarkably, the Grignard
reagent 2 underwent Negishi cross-couplings[15] with aryl
bromides bearing unprotected anilines,[16] such as 4-bromo-
The SF5 group is sensitive to polar organometallic species
such as organolithiums, for example 1-bromo-4-
(pentafluoro
G
ACHTUNGTRENNUNG
À788C. In contrast, the reaction with tBuLi in diethyl ether
at À788C produced the desired lithium intermediate without
side reactions.[7] Additionally, halogen–lithium exchange re-
actions require low temperatures and are not compatible
with several important functional groups, such as ketones,
aldehydes, or esters. In contrast, the halogen–magnesium ex-
change has been found to be the method of choice for pre-
paring new functionalized organomagnesium reagents of
considerable synthetic utility.[8] Recently, we have developed
several preparations of aryl- and heteroarylzinc and -magne-
sium compounds displaying high functional group compati-
ACHTUNGTRENNUNG
reagent 2 with ethyl cyanoformate (3e) yielded the SF5-sub-
stituted ester 4e in 80% yield (Table 1, entry 5). Addition of
2 to electron-poor aldehydes, such as 2,3-dichlorobenzalde-
hyde (3 f) as well as electron-rich aldehydes such as 4-me-
thoxybenzaldehyde (3g) led to the SF5-functionalized alco-
hols 4 f and 4g in 81–84% yield (Table 1, entries 6 and 7).
After transmetalation with CuCN·2LiCl (1.1 equiv),[17] sub-
stitution with benzoyl chloride (3h) provided the ketone 4h
in 84% yield (Table 1, entry 8).
bility. These include
iPrMgCl·LiCl,[8] and directed metalation of aromatics and
heteroaromatics using kinetically highly active bases such as
a
Br/Mg exchange using
Also, the SF5 substituent showed a good compatibility in
the
performance
of
directed
metalations
using
G
TMP2Mg·2LiCl. Thus, the treatment of the SF5-substituted
benzoic acid ethyl ester 4e with TMP2Mg·2LiCl led to the
functionalized arylmagnesium reagent 5 after 12 h at À408C
in approximately 82% yield[13] (Table 2). After transmetala-
tion with ZnCl2 (1.1 equiv) the resulting zinc reagent under-
went a Negishi cross-coupling[15] with 1-iodo-4-methoxyben-
zene (3i) or 4-iodobenzonitrile (3j) in the presence of 2%
TMPMgCl·LiCl
(TMP=2,2,6,6-tetramethylpiperidyl),[9]
TMP2Mg·2LiCl,[10]
TMPZnCl·LiCl,[9,11]
and
TMP2Zn·2MgCl2·2LiCl.[12] Herein, we report a range of or-
[a] A. Frischmuth, A. Unsinn, K. Groll, Prof. Dr. P. Knochel
Department Chemie
[PdACHTNUTGRNEUNG
(dba)2] (dba=dibenzylideneacetone) and 4% tfp[18]
(tfp=tri-(2-furyl)phosphine) (258C, 12 h), providing the
SF5-substituted biphenyl derivatives 6a and 6b in 52–83%
yield (Table 2, entries 1 and 2). A copper-catalyzed allyla-
tion (20% CuCN·2LiCl) with 3-bromocyclohexene (3k)
provided the trisubstituted benzene 6c in 70% yield
(Table 2, entry 3). Furthermore, a CuI-mediated acylation
with benzoyl chloride (3h) led to the corresponding keto-
ester 6d in 87% yield (Table 2, entry 4).
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax : (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[b] Dr. H. Stadtmꢁller
Boehringer Ingelheim RCV GmbH & Co KG
Doktor-Bçhringer-Gasse 5-11, 1121 Wien (Austria)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201485.
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Table 1. Products of type
iPrMgCl·LiCl followed by reaction with various electrophiles.
4
obtained by Br/Mg exchange with
Table 2. Products of type 6 obtained by directed metalation of the ethyl
benzoate 4e using TMP2Mg·2LiCl followed by quenching with electro-
philes.
Entry
Electrophile
Product[a]
Entry
Electrophile
Product[a]
1
2
3
3a
3b
3c
4a: 83%[b]
4b: 79%[b]
4c: 88%[c]
1
2
3i
3j
6a: 52%[b]
6b: 83%[b]
3
4
3k
3h
6c: 70%[c]
6d: 87%[d]
4
5
3d
3e
4d: 71%[c]
4e: 80%
[a] Isolated yields of analytically pure product. [b] Cross-coupling condi-
tions: ZnCl2 (1.1 equiv) / 2% [Pd(dba)2], 4% tfp, 238C, 12 h. [c] 20%
AHCTUNGTRENNUNG
CuCN·2LiCl was added. [d] CuCN·2LiCl (1.1 equiv) was added.
diarylamines. Br/Mg exchange on 1-iodo-4-methoxybenzene
or 4-iodobenzoic acid ethyl ester with iPrMgCl·LiCl[8] (THF,
À208C, 0.5 h) produced the corresponding functionalized
Mg reagents 7a and b. These organometallics reacted
smoothly with 1-bromo-3-nitro-5-pentafluorosulfanylben-
zene (8), prepared[20] from 3-nitro-5-pentafluorosulfanylben-
zene. After reductive treatment with FeCl2/NaBH4, the SF5-
substituted diarylamines 9a and 9b were obtained in 66–
82% yield (Scheme 1).
6
3 f
4 f: 81%
7
8
3g
3h
4g: 84%
4h: 84%[d]
Heterocyclic building blocks are ubiquitous in medicinal
chemistry. Thus, we have prepared SF5-substituted indoles.
Starting from 2-bromo-5-(pentafluorosulfanyl)aniline[21]
(10), the synthesis of 6-pentafluorosulfanyl-1H-indole (11)
was achieved in two steps (Scheme 2). First, we performed
a Sonogashira cross-coupling[22] by treating 2-bromoaniline
10 with (trimethylsilyl)acetylene (1.5 equiv, 508C, 12 h), pro-
[a] Isolated yields of analytically pure product. [b] Cross-coupling condi-
tions: ZnCl2 (1.1 equiv) / 2% PEPPSI-iPr. [c] Cross-coupling conditions:
ZnCl2 (1.1 equiv)
/
2% PdACTHGNURETNNU(G OAc)2, 4% S-Phos, 238C, 12 h.
[d] CuCN·2 LiCl (1.1 equiv) was added.
Arylamines are an important class of pharmaceuticals,
due to their ability to undergo highly specific interactions
with proteins. Therefore, we
have also prepared SF5-substi-
tuted arylamines. Recently, we
have shown that the amination
of arylmagnesium reagents with
nitroarenes provides after re-
ductive workup polyfunctional
diarylamines.[9,19] This method
proved to be well suited for the
Scheme 1. Synthesis of diarylamines 9a and 9b using arylmagnesium halides 7a and 7b and the SF5-substituted
preparation of SF5-substituted nitroarene 8.
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SF5-Substituted Aryl and Heteroaryl Derivatives
COMMUNICATION
viding the SF5-substituted 2-
((trimethylsilyl)ethynyl)aniline
(11) in 89% yield. A subse-
quent cyclization reaction was
performed by treatment with
KH (2.5 equiv) in N-methylpyr-
rolidone (NMP) (238C, 3 h) to
afford the indole 12 in 83%
Scheme 2. Synthesis of the SF5-substituted indole 12 and subsequent Boc-protection. Reagents and conditions:
yield.[23] The indole 12 was a) Fe powder (6.0 equiv) HCl/EtOH 1:20, 238C, 1 h, 91%; b) NBS (1.0 equiv), dioxane, 238C, 8 h, 79%; c)
Boc2O (1.5 equiv), 7% DMAP, 238C, 1.5 h.
readily protected at nitrogen
with Boc2O leading to the N-
Boc indole 13 in 94% yield
(Scheme 2).
Further functionalization of
the N-protected indole 13 could
be
achieved
by
using
TMPMgCl·LiCl.[9] The selective
magnesiation of 13 at position 2
of the indole ring with
TMPMgCl·LiCl (1.1 equiv, 08C,
0.5 h), and subsequent trapping
with cyanoformic acid ethyl
ester (3e, 1.1 equiv, À308C,
1 h), afforded the N-protected
ethyl 6-(pentafluorosulfanyl)-
1H-indole-2-carboxylate 14 in
93% yield. Subsequent treat-
ment of the indole 14 with
Scheme 3. Functionalization of position 2 and 3 of the N-protected indole 13 by using TMPMgCl·LiCl.
TMPMgCl·LiCl (1.1 equiv, À408C, 2 h) led to a fast magne-
siation at position 3 (Scheme 3).
After the transmetalation with ZnCl2 (1.1 equiv), Negishi
cross-coupling reactions[15] (2% PEPPSI-iPr,[14] 238C, 10 h)
with 4-iodo-2,6-dimethoxypyrimidine or 4-iodobenzonitrile
provided the corresponding indoles 15a and 15b in 62–75%
yield. Alternatively, a transmetalation with CuCN·2 LiCl
(1.0 equiv) allows an efficient benzoylation (PhCOCl
(1.2 equiv), À408C, 12 h) affording smoothly the 2,3-disub-
stituted indole 15c in 87% yield (Scheme 3).
Besides indoles, benzo[b]thiophenes are of particular in-
terest, as they are potential drug candidates[24] and are also
widespread in materials chemistry.[25] Functionalized ben-
zo[b]thiophenes can be prepared by the intramolecular
copper-catalyzed
ACHTUNGTRENNUNG
carbomagnesiation
of
alkynyl-
(aryl)thioethers.[26] Herein, we have applied this method to
the synthesis of SF5-substituted, functionalized benzo[b]thio-
phenes of type 16 (Scheme 4). The readily available SF5-sub-
stituted 1,2-bromoiodoarene 17[27] was converted to the cor-
responding organic disulfide 18 by a I/Mg-exchange reaction
(iPrMgCl·LiCl,[8] À808C, 10 min), subsequent transmetala-
tion with ZnCl2, and reaction with sulfur monochloride.[28]
The sulfonothioate 19 was obtained by treating the disulfide
18 with iodine and sodium benzenesulfinate.[29] This sulfono-
thioate reacted with trimethylsilylethynylmagnesium chlo-
Scheme 4. Reaction sequence towards the SF5-substituted alkynyl-
(aryl)thioether 20 and subsequent cyclization/allylation and acylation re-
AHCTUNGTRENNUNG
action sequence. Reagents and conditions: a) iPrMgCl·LiCl (1.05 equiv),
THF, À808C, 10 min; b) ZnCl2 (1.1 equiv), À808C; 10 min; c) S2Cl2
(0.49 equiv), À808C, 10 min; d) PhSO2Na (3.2 equiv), I2 (2.0 equiv),
CH2Cl2, 238C, 48 h; e) ethynyltrimethylsilane (1.5 equiv), iPrMgCl·LiCl
(1.2 equiv), THF, À608C, 15 min; f) iPrMgCl·LiCl (1.1 equiv), THF,
238C, 1 h; g) CuCN·2 LiCl (1.1 equiv), 238C, 12 h; h) E+ (0.8 equiv),
238C, 12 h.
ride providing the desired alkynylACHTUNTRGNEUNG(aryl)thioether 20 in 80%
yield. Thus, the treatment of the thioether 20 with
iPrMgCl·LiCl (1.1 equiv, 238C, 1 h) provided the corre-
sponding magnesium reagent 20a. In the presence of stoi-
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chiometric amounts of CuCN·2LiCl cyclization occurred at
238C within 12 h producing the copper reagent 20b. A sub-
sequent allylation reaction with 2-(bromomethyl)acrylic acid
ethyl ester (0.8 equiv) afforded the polyfunctional benzo-
thiophene 16a in 70% yield. Similarly, the acylation with
furan-2-carbonyl chloride (0.8 equiv) provided the acylated
benzothiophene 16b in 64% yield.
In conclusion, we have prepared a range of polyfunctional
SF5-substituted aromatic and heterocyclic compounds using
zinc and magnesium intermediates. A library of SF5-substi-
tuted molecules should become available using these
organoACHTUNGTRENNUNGmetallic methodologies and should allow their use for
the discovery of new biologically active compounds.
Acknowledgements
The research leading to these results has received funding from the Euro-
pean Research Council under the European Communityꢃs Seventh
Framework Programme (FP7/2007–2013) ERC grant agreement no.
227763. We thank Boehringer Ingelheim RCV GmbH & Co KG for the
generous gift of chemicals.
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Keywords: C–C
substituents
organometallic compounds
coupling
heterocyclic compounds
reactions
·
fluorinated
metalation ·
·
·
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SF5-Substituted Aryl and Heteroaryl Derivatives
COMMUNICATION
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Received: April 30, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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P. Knochel et al.
C–C Coupling Reactions
A. Frischmuth, A. Unsinn, K. Groll,
H. Stadtmꢀller, P. Knochel* &&&& — &&&&
Polyfunctional SF5-substituted cycles:
Several organometallic sequences
using zinc, copper, and magnesium
intermediates were developed to pre-
pare a broad range of SF5-substituted
aromatic and heterocyclic compounds
of potential interest for pharmaceutical
applications.
Preparations and Reactions of SF5-
Substituted Aryl and Heteroaryl
Derivatives via Mg and Zn Organome-
tallics
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www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!