Iron-Catalyzed Cross-Coupling of 1-Alkynylcyclopropyl Tosylates and Related Substrates

Article abstract of DOI:10.1002/adsc.201600357

1-Alkynylcyclopropyl tosylates react with alkylmagnesium halides in the presence of catalytic ferric acetylacetonate [Fe(acac)₃] under net propargylic substitution; allene formation, which is the prevalent reactivity mode of propargylic substra

Full text of DOI:10.1002/adsc.201600357

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DOI: 10.1002/adsc.201600357
Very Important Publication
Iron-Catalyzed Cross-Coupling of 1-Alkynylcyclopropyl Tosylates
and Related Substrates
Daniel J. Tindall,a Helga Krause,a and Alois Fꢀrstnera,*
a
Max-Planck-Institut fꢀr Kohlenforschung, 45470 Mꢀlheim/Ruhr, Germany
Fax : (+49)-208-306-2994; phone: (+49)-208-306-2342; e-mail: fuerstner@kofo.mpg.de
Received: April 5, 2016; Revised: May 2, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600357.
À
Abstract: 1-Alkynylcyclopropyl tosylates react with
alkylmagnesium halides in the presence of catalytic
ferric acetylacetonate [Fe(acac)3] under net propar-
gylic substitution; allene formation, which is the
prevalent reactivity mode of propargylic substrates
otherwise, was noticed as a side reaction only when
branched alkyl- or aryl-Grignard reagents were
used. These transformations represent the first suc-
cessful iron-catalyzed cross-coupling reactions of
tert-alkyl electrophiles.
successfully engaged in this type of C C bond form-
ing reaction;[2–9] tert-alkyl halides, however, basically
fail to react.[17] Some open mechanistic issues apart,
there is substantial evidence for radical intermediates
along the pathway which are most likely formed by
single electron transfer (s.e.t.) from a loaded iron cat-
[13–15,18]
À
alyst to the low-lying LUMO of the C X bond.
As alkyl sulfonates are much poorer electron
acceptors, they are unreactive unless the mixture is
supplemented with halide ions that substitute the sul-
fonate in the first place before a triggering s.e.t. can
occur.[19–22]
Keywords: cross-coupling; cyclopropanes; Grignard
reagents; iron; propargylic substitution
In view of the foregoing, it was surprising to find
that the 1-alkynylcyclopropyl tosylate 1a couples with
MeMgCl in the presence of Fe(acac)3 as the precata-
lyst with net replacement of the sulfonate group to
give 2a in good yield under notably mild conditions
Iron possesses practical benefits more befitting an (Scheme 1). The reaction forms a quaternary center
alkali or earth-alkali metal, while displaying the and proceeds even though the substrate lacks a halide
unique reactivity of a d-block element. This attractive leaving group;[23] it hence differs from essentially all
profile nurtures a rapidly growing interest in the de- other iron-catalyzed alkyl–alkyl coupling reactions
velopment of iron-based catalysts for applications known to date.[17,24,25] The fact that the corresponding
that are currently dominated by less benign and/or allene 3a was not observed is particularly noteworthy,
much more expensive (noble) metal catalysts. Cross- since propargylic substrates like 4 and 6 react in an
coupling is an important such area: despite the endur- SN2’-type manner to afford the corresponding allene
ing primacy of palladium catalysis,[1] the development derivatives 5 and 7 when exposed to Grignard re-
of iron-based alternatives prospers since the turn of agents under iron catalysis (Scheme 2).[26,27] Com-
the millennium.[2–9] At that time, early lead findings pounds with a small ring flanking the triple bond also
were refined, generalized and turned into broadly ap- do so, as illustrated by the syn-selective ring opening
plicable methods,[10,11] which find increasing resonance
in academic as well as industrial contexts.
Yet, these studies also showed that iron is not only
a possible substitute for palladium in certain cases,
but enables transformations that are difficult to ac-
complish with traditional noble metal catalysts. The
remarkable ease with which even the simplest iron
salts or iron complexes promote the cross-coupling of
Grignard reagents (or related nucleophiles) with alkyl
halides is representative.[12] Since this reactivity mode
Scheme 1. Lead finding of an iron-catalyzed cross-coupling
of a 1-alkynylcyclopropyl tosylate with net replacement of
was discovered in 2004,[13–16] a host of (functionalized)
primary and secondary (cyclo)alkyl halides has been the sulfonate group.
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Table 1. Iron-catalyzed cross-coupling of different Grignard
reagents with 1-alkynylcyclopropyl tosylates.[a]
Entry Product
R1
Yield [%][b]
70
1
2
3
4
2a Ph
2b (CH2)2OBn 76
2c (CH2)3OTBS 83
2a Ph
44[c]
5
6
7
2d Ph
2e (CH2)2OBn 86
2f (CH2)3OTBS 87
90
8
9
2g Ph
2h butyl
86
88
10
11
12
2i (CH2)2OBn 74
2j (CH2)3OTBS 80
2k SiMe3
78
13
14
15
16
2l Ph
2m CH2OPh
2n (CH2)2OBn 73
2o (CH2)3OTBS 57
76
76[d]
Scheme 2. Literature examples of allene formation from
propargyl derivatives under iron catalysis.
17
18
2p (CH2)3OTBS 49[e]
of alkynyl epoxide 8 with formation of the corre-
sponding allenol 9.[28,29] Even the alkynyl cyclopro-
pane derivative 10 furnished allene 11 by cleavage of
[30]
À
the activated C C bond. The pronounced bias for
allene formation is also manifest in the fact that 1-al-
kynylcyclopropyl derivatives usually convert into vi-
nylidenecyclopropanes when reacted with RMgX in
the presence of CuI.[31] Only palladium-based cata-
lysts are known to give more variable outcomes:
while 1a was reported to decompose when treated
with MeZnCl in the presence of Pd(0), 1-alkynylcy-
clopropyl chlorides afforded mixtures of substituted
and/or reduced cyclopropane derivatives as well as al-
lenes in varying ratios.[32]
2q (CH2)3OTBS 59[d]
19
20
2r Ph
2s (CH2)2OBn 37[g]
64[f]
[a]
All reactions were performed on a 0.2–1.1 mmol scale in
THF at À208C to room temperature with 5 mol% cata-
lyst loading using 1.3–1.5 equivalents of R2 MgX relative
to 1.
The unusual propensity of 1-alkynylcyclopropyl to-
sylates to react by net substitution of the tertiary leav-
ing group under iron catalysis is fairly general
[b]
[c]
[d]
Isolated yield of pure 2.
Using MeLi instead of MeMgCl.
The crude material contained traces of the corresponding
allene by-product.
À
(Table 1). As expected, C C bond formation is con-
tingent on the presence of the iron catalyst; no con-
version was observed when 1 (R1 =butyl) was treated
with C6H13MgBr in the absence of Fe(acac)3 under
otherwise identical conditions. Various primary alkyl-
Grignard reagents cross-couple well with an assort-
ment of substrates of this type, all of which are readily
[e]
[f]
The crude product is a 2p:3pꢀ4:1 mixture; 12% of pure
3p were isolated by HPLC.
The crude product is a 2r:3rꢀ7.3:1 mixture; 9% of pure
3r were isolated by HPLC.
[g]
The crude product is a 2s:3sꢀ1.3:1 mixture; 29% of pure
3s were isolated by HPLC.
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accessible from commercial 1-ethoxy-1-trimethylsilyl- that the alignment of the antibonding s*-orbital of
À
oxycyclopropane according to a literature proce- the C OTs bond with one of the two orthogonal p-
dure.[33,34]
Interestingly,
the
reactions
of systems of the alkyne plays a role in that it facilitates
Me3SiCH2MgCl proceeded much more slowly (4– ionization (Figure 1).[43] While the overall conforma-
48 h) than those of MeMgX (ꢁ1 h), although they are tion of the corresponding alkenyl derivative 16 is very
equally clean and productive. Since methyl donors similar (Figure 2),[43] it is of note that the p-cloud is
afford iron-ate complexes in the first place,[35] this now orthogonal to the antibonding orbital of the leav-
striking reactivity difference is thought to reflect the ing group. Speculation apart, olefinic substrates such
poor transferability of the trimethylsilylmethyl unit as 16 are less auspicious coupling partners than their
caused by the b-silicon effect on the metal center.[36] sister compounds 1 endowed with alkynyl substitu-
MeMgX could be replaced by MeLi, although at ents; 16 does react with MeMgCl in the presence of
a net expense of yield (entry 4).[37] The slim cyclopro- Fe(acac)3 to give the corresponding methylated prod-
pylmagnesium bromide also worked well (entry 18), uct 17 in good yield only if the reagent is slowly
whereas bulkier sec-alkyl- as well as aryl-Grignard re- added (Scheme 3); products 21–23 were obtained
agents furnished appreciable amounts of allene by- analogously (the lower yields are partly due to the
products. This trend was enhanced by the presence of
donor sites in vicinity to the alkyne moiety (compare
entries 19 and 20).
The increasing attention paid in the literature to
the (1-methylcyclopropyl)ethynyl group underscores
the significance of this new transformation. This struc-
tural motif can bring metabolic advantages over an
ordinary tert-butyl substituent and – as a yet fairly un-
derutilized unit – may provide freedom to operate. A
series of possible anti-HIV drug candidates of type 12
related to Efavirenzꢂ illustrates these notions,[38] as do
compounds of type 13 or 14 that were patented for
the potential treatment of hepatitis C[39,40] or cystic
fibrosis[41] as well as for crop protection purposes
(Figure 3).[42] Moreover, natural products such as 15
feature this substructure. The new iron-catalyzed pro-
cedure provides ready access and potentially enables
late-stage variations of this important motif.
Although the mechanism of the alkyl–alkyl cross-
coupling reaction described herein is currently un-
known, it is certain that the triple bond in 1 is more
than an innocent by-stander. It is tempting to assume
Figure 2. Structure of compound 16 in the solid state.
Figure 3. Representative examples of bioactive compounds
comprising a (1-methylcyclopropyl)ethynyl group.
Figure 1. Structure of compound 1a in the solid state.
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Scheme 3. Iron-catalyzed reactions of 1-alkenyl-cyclopropyl tosylates: a) RMgX, Fe(acac)3 (5 mol%), THF, 08C.
volatility of these hydrocarbons).[44] Notably, however, product 19 derives almost certainly from an organo-
attempted coupling of 16 with other Grignard re- metallic precursor. This conclusion can be drawn
agents led to product mixtures comprising substantial from the control experiment depicted in Scheme 3 in
amounts of reduced and dimeric compounds such as which 16 was treated with [D5]-EtMgBr in non-deu-
19 and 20; the results for (deuterated) EtMgBr are terated THF. The fact that the reduced product was
representative. The crucial role of the p-system next fully deuterated at the branching point (ꢂ95% deute-
to the tosylate leaving group is also evident from the rium incorporation, NMR) likely indicates an ethylir-
fact that the saturated substrate 24 as well as the 1-ar- on precursor,[47] which can either cross-couple to give
ylcyclopropyl derivative 25 failed to react under oth- [D5]-18 or decay by b-deuteride elimination/reductive
erwise identical conditions.[45]
coupling with formation of [D]-19.
The constitution of dimer 20 with two intact cyclo-
In summary, we report the first case of an iron-cata-
propyl rings is unambiguous (Figure 4).[43] While the lyzed cross-coupling reaction with tertiary alkyl
formation of this compound might suggest the inter- derivatives as electrophilic partners. As such, the
vention of a radical intermediate,[46] the reduced transformation helps increase the realm of iron catal-
ysis[48] and provides ready access to important struc-
tural motifs that are cumbersome to make otherwise.
Further investigations into the genuine catalytic prop-
erties of this cheap and benign base metal are cur-
rently underway and will be reported in due course.
Experimental Section
Representative Procedure for the Iron-Catalyzed
Cross-Coupling Reactions (Table 1, Entry 11)
Hexylmagnesium bromide (2M in THF, 0.24 mL,
0.480 mmol) was added over the course of 5 min to an
orange solution of tosylate 1 [R1 =(CH2)3OTBS] (152 mg,
0.372 mmol) and Fe(acac)3 (7 mg, 5 mol%, 0.020 mmol) in
THF (4 mL) at À208C. After stirring for 10 min at this tem-
perature, the brown mixture was diluted with saturated
Figure 4. Structure of compound 20 in the solid state.
aqueous NH4Cl (5 mL) and the aqueous phase extracted
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with EtOAc (3ꢃ5 mL). The combined extracts were dried
over Na2SO4 and concentrated, and the residue was purified
by flash chromatography (silica, hexane) to give tert-
butyl{[(5-(1-hexylcyclopropyl)pent-4-yn-1-yl]oxy}dimethylsi-
lane as a colorless liquid; yield: 96 mg (80%). 1H NMR
(400 MHz, CDCl3): d=3.68 (t, J=6.2 Hz, 2H), 2.21 (t, J=
7.0 Hz, 2H), 1.70–1.62 (m, 2H), 1.57–1.47 (m, 2H), 1.35–
1.23 (m, 8H), 0.89 (s, 9H), 0.88 (t, J=7.0 Hz, 3H), 0.79–0.75
(m, 2H), 0.52–0.47 (m, 2H), 0.05 (s, 6H); 13C NMR
(100 MHz, CDCl3): d=85.4, 76.0, 61.9, 38.7, 32.3, 32.1, 29.3,
28.0, 26.1, 22.8, 18.5, 15.3, 15.2, 14.3, 12.1, À5.2; IR (film):
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other alkyl-Grignard reagents, however, led to partial
n˜ =2954, 2927, 2856, 1470, 1463, 1254, 1103, 833, 774 cmÀ1
;
MS (EI): m/z (%)=307 (1), 265 (100), 191 (14), 189 (38),
161 (6), 151 (5), 139 (3), 133 (4), 119 (26), 105 (16), 101 (18),
93 (10), 91 (19), 79 (13), 75 (96), 59 (15), 43 (11); HR-MS
(ESI+): m/z=345.25853, calcd. for C20H38OSiNa [M+Na]+:
345.25841.
The entire experimental section, including characteriza-
tion data of all new compounds, is contained in the Support-
ing Information.
À
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Acknowledgements
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[48] For another recently discovered reactivity mode of iron
catalysts that has no equivalent in noble metal catalysis,
see: a) C.-L. Sun, A. Fꢀrstner, Angew. Chem. 2013,
125, 13309–13313; Angew. Chem. Int. Ed. 2013, 52,
13071–13075; b) C.-X. Zhuo, A. Fꢀrstner, Angew.
Chem. 2016, 128, 6155–6160; Angew. Chem. Int. Ed.
2016, 55, 6051–6056.
[37] In contrast, the use of Et2Zn in the presence of excess
MgBr2 resulted in slow allene formation.
[38] Bristol-Myers-Squibb, WO Patent WO2004/13110A1,
2004.
Adv. Synth. Catal. 0000, 000, 0 – 0
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COMMUNICATIONS
Iron-Catalyzed Cross-Coupling of 1-Alkynylcyclopropyl
Tosylates and Related Substrates
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Adv. Synth. Catal. 2016, 358, 1 – 7
Daniel J. Tindall, Helga Krause, Alois Fꢀrstner*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!