Iron-Catalyzed Cross-Coupling Reactions: Efficient Synthesis of 2, 3-Allenol Derivatives

Article abstract of DOI:10.1002/anie.200352441

Reliable chirality transfer is one of the major advantages of a novel synthesis of 2,3-allenols from propargyl epoxides (see scheme) catalyzed by inexpensive and environmentally benign iron salts. The reactions proceed very rapidly in excellent yields and

Full text of DOI:10.1002/anie.200352441

Angewandte
Chemie
Scheme 1. Preparation and iron-catalyzed reaction of a nonterminal
propargyl bromide with a Grignard reagent.
Iron-Catalyzed Allenol Formation
Iron-Catalyzed Cross-Coupling Reactions:
Efficient Synthesis of 2,3-Allenol Derivatives**
together with compound 4 formed by direct SN2-substitution.
The ee of the latter was only 55%, thus showing that a
considerable loss in enantiomeric purity accompanied this
overall transformation.
Alois Fürstner* and María MØndez
Convinced of the preparative advantages of iron salts as
user-friendly, inexpensive, and virtually nontoxic precata-
lysts,[7] however, various propargyl derivatives were screened
in the search for better substrates. Gratifyingly, we found that
propargyl epoxides perform exquisitely well. They are easily
prepared in optically active form[12] and react with different
Grignard reagents with exceptional efficiency in the presence
of catalytic amounts of simple iron salts, preferentially the
nonhygroscopic [Fe(acac)3]. First and utmost, the central
chirality of these substrates is transferred to the axial chirality
of the resulting 2,3-allenols with high fidelity, as can be seen
from the examples compiled in Scheme 2.
The reactions are virtually instantaneous, even at low
temperatures (45 min), the required catalyst loading is low
(3–5 mol%),[13] no extra ligands are necessary, the yields are
good to excellent, and the substrate scope is sufficiently
broad. Importantly, propargyl epoxides with terminal or
nonterminal alkyne units react with similar ease (Table 1).
Moreover, the direct attack of the Grignard reagent at the
epoxide ring[14] remains insignificant in all but the most
activated cases (Table 1, entries 17 and 21).
Allenes in general and 2,3-allenol derivatives in particular are
versatile building blocks for advanced organic synthesis
because of the reactivity inherent to their axially chiral
backbones.[1] They are usually prepared by SN2’-type reactions
of propargylic substrates with organocopper reagents.
Although this methodology has reached a high degree of
sophistication and met with considerable success,[2] a liter-
ature survey shows that the stoichiometric regimen continues
to prevail over the catalytic manifold in most applications.[1–3]
Furthermore, strongly donating ligands to copper such as
PBu3 or P(OMe)3 are required for efficient chirality transfer
from the propargylic substrate to the incipient allene and/or
to avoid the formation of reduction products derived from
formal hydride delivery.[1f,4,5] Finally, a certain propensity of
cuprates to racemize enantiomerically enriched allenes has
been documented on several occasions.[6]
During our recent studies on iron-catalyzed cross-cou-
pling reactions,[7] we became aware of an early, yet virtually
inconsequential, report of Pasto et al. on the use of simple
iron salts as precatalysts for the formation of allenes from
propargylic halides and Grignard reagents.[8–10] In an attempt
to apply this method, however, its limitations became
immediately apparent (Scheme 1). Specifically, conversion
of the scalemic propargyl alcohol 1 (78% ee)[11] into the
corresponding bromide 2 followed by reaction with p-
MeOC6H4MgBr in the presence of [Fe(acac)3] catalyst
furnished the desired allene 3 as the minor product only,
[*] Prof. A. Fürstner, Dr. M. MØndez
Max-Planck-Institut für Kohlenforschung
45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2994
E-mail: fuerstner@mpi-muelheim.mpg.de
[**] Part 4. For Part 3, see reference [7b]. Generous financial support by
the Deutsche Forschungsgemeinschaft (Leibniz program) and the
Fonds der Chemischen Industrie is gratefully acknowledged. M.M.
thanks the Alexander-von-Humboldt-Foundation for a fellowship.
Scheme 2. Chirality transfer experiments.
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DOI: 10.1002/anie.200352441
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Communications
Table 1: Iron-catalyzed synthesis of 2,3-allenols from propargyl epoxides.[a]
Entry
Substrate
R1
R2MgX
Major product
Solvent
syn/anti
Yield [%]
1
2
3
4
5
6
7
8
H
H
H
Me
Me
Me
Me
Me
Me
Ph
C6H13MgBr
PhMgBr
toluene
toluene
toluene
Et2O
Et2O
Et2O
Et2O
toluene
Et2O
Et2O
Et2O
78:22
75:25
55:45
86:14
78:22
50:50
84:16
90:10
66:34
65:35
92:8
72[b]
83
71
MeMgBr
C6H13MgBr
C6H13MgBr
C6H13MgBr
iPrMgCl
iPrMgCl
PhMgBr
MeMgBr
C6H13MgBr
93
75[c]
54[d]
79
70
98
9
10
11
69
CH2OH
65[e]
12
Me
C6H13MgBr
toluene
80:20
73
13
14
Me
Me
C6H13MgBr
iPrMgCl
toluene
toluene
88:12
84:16
80
79
15
16
17
18
Me
Me
Me
Me
C6H13MgBr
C6H13MgBr
iPrMgCl
toluene
Et2O
toluene
Et2O
92:8
62
75:25
86:14
60:40
90
75[f]
89
iPrMgCl
19
20
C5H11
C5H11
iPrMgCl
iPrMgCl
toluene
Et2O
91:9
75:5
94
64
21
C5H11
EtMgBr
toluene
82:18
55[g]
[a] The reactions were carried out at À58C in the presence of [Fe(acac)3] (3–5 mol%) precatalyst and Grignard reagent (1.3 equiv), unless stated
otherwise. [b] Fe–salen precatalyst. [c] À308C. [d] À608C. [e] Grignard reagent (2.3 equiv). [f] A by-product (9%) was isolated that is formed by direct
attack of the Grignard at the epoxide ring of the substrate. [g] In addition to the allenol, approximately 15% of by-products were formed from direct
attack of the Grignard reagent at the epoxide ring of the substrate.
As can be seen from Table 1, the syn-configured 2,3-
allenols are invariably formed as the major products.[15]
Remarkably, this stereochemical outcome is opposite to that
usually observed in reactions of propargyl epoxides with
organocopper reagents,[4,6,16] which furnish the anti-config-
ured allenols, except when carried out under “ligand-free”
conditions in the presence of excess TMSCl.[4] Although the
efficiency of the iron-catalyzed allenol formation is largely
independent of the solvent used, the diastereoselectivity is
higher in toluene than in Et2O. This consistent trend (Table 1,
entries 7/8, 15/16, 17/18, 19/20) is tentatively interpreted in
terms of a “directed” delivery of the nucleophile to the
alkyne,[17] which occurs only after the catalyst and/or the
Grignard reagent has been coordinated to the oxygen atom of
the substrate. Such a precoordination is likely more pro-
nounced in a hydrocarbon solvent than in an ether medium
(Scheme 3).
Scheme 3. Proposed stereochemical rationale for the preferential for-
mation of syn-configured 2,3-allenol derivatives by “directed” delivery
of the nucleophile R.
less clear (Table 1, entries 4–6). Detailed mechanistic inves-
tigations will be necessary to shed light on this unusual
behavior, which must include studies on the nature of the still
elusive (and most likely highly reduced)[7] but exceptionally
efficient iron catalyst formed in situ upon mixing of
[Fe(acac)3] with an excess of an organomagnesium reagent.
Investigations along these lines and further applications of
iron-catalyzed cross-coupling reactions are currently under-
way and will be reported in due course.[18]
The reasons, however, why the diastereoselectivity
decreases upon lowering the reaction temperature are far
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Chemie
Waterhouse, R. H. Shults, G. F. Hennion, J. Org. Chem. 1978, 43,
1385 – 1388.
Experimental Section
iPrMgCl (2m in Et2O, 0.42 mL, 0.83 mmol) was transferred by syringe
into a solution of 1-prop-1-ynyl-9-oxa-bicyclo[6.1.0]nonane (105 mg,
0.64 mmol) and [Fe(acac)3] (11 mg, 0.03 mmol) in toluene (14 mL) at
À 58C under Ar, causing an immediate color change from bright red
to dark brown/black. After stirring for 5 min, the mixture was
quenched with NH4Cl (5 mL) and diluted with Et2O (10 mL), the
layers were separated, and the aqueous phase was extracted with
Et2O (3 ” 5 mL). The combined organic layers were dried over
MgSO4, and the residue was purified by flash chromatography (5:1
pentane/Et2O) to provide 2-(2,3-dimethylbut-1-enylidene)-cycloocta-
[9] A. S. K. Hashmi, G. Szeimies, Chem. Ber. 1994, 127, 1075 – 1089.
[10] For reports on the reaction of certain allylic substrates under
iron catalysis, see: a) A. Yanagisawa, N. Nomura, H. Yamamoto,
Tetrahedron 1994, 50, 6017 – 6028; b) A. Yanagisawa, N.
Nomura, H. Yamamoto, Synlett 1991, 513 – 514; c) M. Naka-
mura, K. Matsuo, T. Inoue, E. Nakamura, Org. Lett. 2003, 5,
1373 – 1375; d) M. Nakamura, A. Hirai, E. Nakamura, J. Am.
Chem. Soc. 2000, 122, 978 – 979.
[11] D. E. Frantz, R. Fassler, E. M. Carreira, J. Am. Chem. Soc. 2000,
122, 1806 – 1807.
[12] The enantiomerically enriched substrates used in this study were
prepared by enantioselective oxidation of the corresponding
enynes; see: Z.-X. Wang, G.-A. Cao, Y. Shi, J. Org. Chem. 1999,
64, 7646 – 7650.
[13] Control experiments showed that the iron catalyst is essential;
no productive allenol formation is observed in the absence of
[Fe(acac)3].
[14] Organocopper reagents show a certain tendency to undergo
direct nucleophilic substitution of the epoxide, in particular if the
reaction is carried out with only catalytic amounts of copper, see
comments in reference [1f].
[15] The stereochemical assignment was corroborated by NOE
measurements of the dihydrofuran derivatives formed from
selected allenols upon treatment with AgNO3.[16c] All other
compounds were assigned by analogy. A representative example
is shown below.
~
nol as a colorless oil (100 mg, 75%, d.r. 86:14). IR (KBr): n = 3402,
2931, 2858, 1943, 1115 cmÀ1 1H NMR (400 MHz, CD2Cl2): d = 4.10
;
(dd, J = 7.9, 3.7 Hz, 1H; anti), 4.07 (dd, J = 8.8, 4.0 Hz, 1H; syn), 2.30–
2.10 (m, 2H), 2.05 (m, 1H), 1.87 (m, 1H), 1.71 (s, 3H), 1.70–1.05 (m,
10H), 1.05 (d, J = 1.9 Hz, 3H; syn), 1.04 (d, J = 1.9 Hz, 3H; syn), 1.03
(d, J = 1.9 Hz, 3H; anti), 1.01 ppm (d, J = 1.9 Hz, 3H; anti); syn
isomer: 13C NMR (100 MHz, CD2Cl2; DEPT) d = 197.27 (C), 109.91
(C), 109.67 (C), 72.81 (CH), 33.36 (CH2), 32.99 (CH), 29.66 (CH2),
29.84 (CH2), 26.50 (CH2), 25.92 (CH2), 23.24 (CH2), 22.17 (CH3),
22.04 (CH3), 17.33 ppm (CH3); anti isomer: 13C NMR (100 MHz,
CD2Cl2; DEPT): d = 196.67 (C), 110.58 (C), 110.04 (C), 71.97 (CH),
33.29 (CH2), 33.08 (CH), 29.45 (CH2), 29.18 (CH2), 26.61 (CH2), 26.04
(CH2), 22.92 (CH2), 22.04 (CH3), 21.97 (CH3), 17.37 ppm (CH3); MS
(EI, 70 eV): m/z (%): 208 (10) [M+], 193 (30), 165 (13), 137 (38), 110
(27), 95 (100); HMRS: calcd for C14H24O: 208.1828; found: 208.1827.
Received: July 22, 2003 [Z52441]
Keywords: alkynes · allenes · cross-coupling · epoxides · iron
.
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