Pd-mediated cross-coupling of C-17 lithiated androst-16-en-3-ol-access to functionalized arylated steroid derivatives

Article abstract of DOI:10.1039/C6OB02496C

Herein, we report on Pd-mediated cross-coupling of vinyllithium steroids and aryl bromides to introduce various substituted aryls at C-17 of steroidal frameworks based on the structure of epi-androsterone. Compared to other C-C cross-couplings, this method turned out to be an easy and competitive access to biologically interesting C-17 modified steroids.

Full text of DOI:10.1039/C6OB02496C

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Pd‐mediated cross‐coupling of C‐17 lithiated androst‐16‐
en‐3‐ol – An access to functionalized arylated steroid
derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Vanessa Kocha and Stefan Bräsea,b
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and different phosphine ligands like XPhos or PtBu3 as catalytic
Herein, we report on a Pd‐mediated cross‐coupling of vinyllithium
steroids and aryl bromides to introduce various substituted aryls
at C‐17 of steroidal frameworks based on the structure of epi‐
androsterone. Compared to other C–C cross‐couplings, this
method turned out to be an easy and competitive access to
biologically interesting C‐17 modified steroids.
system enables the alkylation and arylation of different aryl halides
as well as the arylation of different alkenylhalides by employing the
corresponding organolithium reagents.24, 25 This new methodology
attracted interest in our research to find a novel method for
introducing various substituents at C‐17 of a steroidal precursor
within a few steps since many natural products based on a steroidal
framework carry different residues at C‐17. Applying this method
should submit access to biologically active and important steroid
analogues without using any toxic reagents. Herein, we present a
fast and convenient method for introducing different substituted
aryls at C‐17 of a steroid framework via a direct cross‐coupling of
the easily accessible and in‐situ prepared vinyllithium steroid 3.
Palladium‐catalysed cross‐coupling reactions for C–C bond
formation play a key role in all fields of organic synthesis.1‐5 Among
these, Suzuki‐Miyaura with organoboron as organometallic
nucleophile6‐9 and Stille (organotin reagent)10‐15 are mainly used as
they tolerate a huge range of substituents. However, the high
toxicity of organostannanes is often undesirable in particular with
regard to pharmaceutical and medical applications. To over‐come
this disadvantage many coupling reactions based on different
„metal nucleophiles“ such as magnesium (Kumada)16, 17, zinc
20
(Negishi)18 and even silicon (Hiyama‐Denmark)19,
were already
examined. Although organolithium reagents are inexpensive and
either commercially available or easily accessible via halogen‐metal
exchange or direct metallation, the application of organolithium
compounds as cross‐coupling reagents is not well established until
now. Early studies on Pd‐mediated C–C bond formation with
organolithium reagents as nucleophile by Murahashi demonstrated
the limitations of this method resulting from the high reactivity and
poor selectivity of organolithium reagents in general.21‐23 To
overcome these difficulties, Feringa et al.24, 25 recently reported on
a novel protocol under mild conditions avoiding the lithium halogen
exchange as well as the competing homocoupling. Using Pd2dba3
Scheme 1: Synthesis of the lithiated steroid 3 and Palladium‐
catalysed cross‐coupling of 3 with aryl bromides.
The lithiated vinyl steroid 3 is easy accessible within 2 steps
(Schema 1) from commercially available epi‐androsterone (1).
Therefore epi‐androsterone (1) was converted to the corresponding
vinyl bromide 2‐Br using first hydrazine to build the hydrazone and
then NBS and pyridine yielding the vinyl bromide 2‐Br in good yields
of 76%. Best results for lithiation of vinyl bromide 2‐Br were
achieved when using 3.1 equivalents of tert‐butyllithium in dry thf.
a. Vanessa Koch, Prof. Dr. Stefan Bräse, Institute of Organic Chemistry, Karlsruhe
Institute of Technology – Campus South, Fritz‐Haber‐Weg 6, 76131 Karlsruhe
(Germany).
b. Prof. Dr. Stefan Bräse, Institute of Toxicology and Genetics, Karlsruhe Institute of
Technology – Campus North, Hermann‐von‐Helmholtz‐Platz 1, 76344 Eggenstein‐
Leopoldshafen (Germany).
†Electronic Supplementary Information (ESI) available: Experimental procedures,
analytical data, 1H and 13C NMR spectra. See DOI: 10.1039/x0xx00000x
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Table 1: Optimization of the reaction conditions.
further improvements. With the optimal conditions in hand, the
scope of the reaction was examined (Table 2) including different
substituted aryl bromides bearing electron‐donating and electron‐
withdrawing groups as well as annulated systems. Regarding the
electron‐donating methyl (hyper‐conjugation) and methoxy (+M‐
effect) group, moderate yields were achieved in the case of ortho‐
and meta‐substituted bromotoluenes whereas para‐substitution
gave the arylated product in good yield of 48% (para‐methyl) and
55% (para‐methoxy).
Entry Starting
material
Conditionsa)
Ratio
4 : 5
Yield of
4 [%]
Table 2: Scope of substrates.
1
2
3
4
5
3
syringe pump (1 h)
3 h at r.t.
‐
traces
3
syringe pump (1 h)
overnight at r.t.
syringe pump (1 h)
overnight at 60 °C
cannulation (30 min)
overnight at r.t.
cannulation (30 min)
overnight at r.t.
1.0 :
3.0
10
3
1.0 :
0.56
1.0 :
0.43
1.0 :
0.28
10
3
44
3‐PG
33
a) Lithiated steroid 3/3‐PG (1.0 eq.) in dry thf was added to a solution of 3‐
bromotoluene (1.3 eq.), Pd2dba3 (5 mol%) and XPhos (20 mol%) in dry
toluene and maintained at the appropriate temperature for the stated
amount of time.
For our initial model reaction (Table 1) we selected 3‐bromotoluene
in
a mixture of toluene and thf as solvent system and
Pd2dba3/XPhos as catalytic system based on the work of Feringa et
al.24, 25 We started our investigations with the usage of a syringe
pump to ensure a slow addition of the highly reactive organolithium
reagent (entries 1 – 3) varying the reaction time and temperature
afterwards. By increasing the reaction time from 3 h to overnight,
we were able to obtain at least 10% instead of traces of the desired
product 4b which was isolated as
a mixture with the
defunctionalized steroid 5. By increasing the reaction temperature
to 60 °C the ratio of the coupled product 4b and the
defunctionalized steroid 5 could be drastically improved (entry 3).
However, best yields were achieved if the freshly prepared lithium
steroid was directly cannulated as thf solution at ‐78 °C (entry 4)
which is reasonable due to the lower stability of 3 compared to the
substrates of the Feringa group. Anyway, even with equimolar
amounts of the catalyst system, yields could not be further
improved indicating that the moderate yields are not a result of an
interrupted catalytic cycle. To exclude that these rather moderate
yields are due to effects caused by the deprotonated hydroxyl
group of the steroid, the OH was protected with a TBDMS group
and again subjected to the developed protocol giving the product
4b‐PG in a better ratio, but unfortunately with no further
enhancement of the yield (entry 5). Along with the described
catalytic system, different palladium sources like Pd(PPh3)4 as well
as alternative phosphine ligands like PtBu3 were tested but without
a This steroid could not be isolated purely (traces of the defunctionalized
steroid 5 could not be completely removed via column chromatography).
Yields were estimated via integration of the signals of the 1H NMR spectrum.
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DOI: 10.1039/C6OB02496C
Scheme 2: Comparison of the presented method with Stille and Suzuki cross‐coupling protocols.
It is worth mentioning that the usage of very polar substituted steroid starting from the vinyl triflate 2‐OTf (see ESI for further
bromides like 1‐bromo‐3,5‐dimethoxybenzene facilitates the information). Applying an optimized protocol for Suzuki cross‐
column chromatography extremely since the separation from the coupling with Pd(PPh3)4 as catalyst and Na2CO3 as base the arylated
deprotected steroid 5 is, in particular for unpolar aryls, challenging product was isolated in 62% yield. When comparing the yield of the
and in some cases not completely possible even after multiple cross‐couplings themselves as well as their overall yield over two
column chromatography. Also, TMS‐protected bromophenol and steps with the herein presented method it becomes obvious that
dimethyl protected bromoaniline could be introduced at C‐17 of the this method is competitive with other well established methods. On
steroid in moderate yields. Furthermore, TMS‐protected alkynes top of it, considering aspects of toxicity, waste disposal and effort
and also acetals were tolerated giving the arylated steroids 4k and the shown coupling is even superior to Stille and Suzuki reaction.
4j in 30% and 36% yield, respectively. In accordance with the results
25
of Feringa et al.24,
nitriles, nitro‐ and keto groups were not
Conclusions
compatible with the organolithium reagent, mainly due to the
formation of 1,2‐addition side products. Furthermore, it could be
proven that an electron‐poor aryl bromide like 1‐bromo‐4‐
fluorobenzene can be introduced successfully to the steroid pattern
even if the yield is not as good as those for electron‐rich aryl
bromides. The arylated systems could be extended to
naphthylbromides which was linked to the steroid in a yield of 54%.
Motivated by this result also a heterocyclic example for an
annulated system like methyl protected 4‐bromoindole was
examined giving the arylated steroid in 25% yield. In order to
evaluate the power of this novel method Stille and Suzuki‐Miyaura
cross‐couplings were performed for comparison starting from the
vinylbromide 2 and the analogous vinyltriflate 2‐OTf (Scheme 2)
whereas para‐bromotoluene served as model bromide. It is
noteworthy that other arylbromides bearing electron withdrawing
(e.g. para‐fluorine) and electron donating substituents (e.g. para‐
methoxy) yield similar results. For the Stille cross‐coupling vinyl
stannyl derivative 2a‐SnBu3 as nucleophile had to be synthesized
In summary, we presented a Pd‐mediated cross‐coupling of
vinyllithium steroids based on the core structure of epi‐
androsterone with different substituted aryl bromides using
the well‐known catalytic system Pd2dba3/XPhos in toluene and
thf as solvent system in order to create new derivatives based
on highly biologically active steroids. Comparing this method
to established methods like Stille or Suzuki cross‐coupling
reactions illustrates its competitiveness and advantages with
respect to toxicity, the amount of waste and overall yields.
Acknowledgements
V. K. gratefully acknowledges the Studienstiftung des
deutschen Volkes for financial support.
Notes and references
Electronic Supplementary Information (ESI) available:
Experimental procedures, analytical data, 1H and 13C NMR
spectra. See DOI: 10.1039/c000000x/
t
via lithiation with BuLi followed by the reaction with tributyltin
chloride giving 2a‐SnBu3 in good yields of 80%. Using Pd(PPh3)4 as
catalyst and LiCl and CuCl as additives the arylated product 4c was
obtained in moderate yield of 58%. For the Suzuki‐Miyaura cross‐
coupling, we installed a pinacolatoboron moiety at C‐17 of the
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