Copper-catalyzed cyclization-fragmentations of enynols

Article abstract of DOI:10.1002/chem.201002314

Pt and Au are going out of fashion: The [Cu(CH₃CN) ₄][BF₄] species effectively catalyzes the cyclization-fragmentation of 5-en-1-yn-3-ols. The reactivity of 6-en-1-yn-4-ols greatly depends on the catalyst used (see scheme). An unusual fragmentation and metathesis reactions of 6-en-1-yn-4-ols have also been detected.

Full text of DOI:10.1002/chem.201002314

DOI: 10.1002/chem.201002314
Copper-Catalyzed Cyclization–Fragmentations of Enynols
Charles Fehr,* Magali Vuagnoux, and Horst Sommer[a]
In 2006, our research group has reported the cost-effec-
rangement, when compared to silver-,[6] gold-,[5b] or plati-
tive cycloisomerization of 5-en-1-yn-3-ols catalyzed by
copper (cyclopropanation/1,2-alkyl shift; Scheme 1)[1] and
related enynol esters.[2] These cyclopropanation reactions,[3]
num-catalysis.
Prior to our work, the silver-promoted cyclization–frag-
mentation reaction of 5-en-1-yn-3-ols had been reported and
correctly interpreted.[6] More
recently, an example of a gold/
silver-catalyzed
cyclization–
fragmentation was fortuitously
observed and rationalized as a
stepwise enyne-Cope rearrange-
ment proceeding via a putative
allenol intermediate.[5b]
Scheme 1. Cycloisomerization with concomitant 1,2-alkyl shift [Cu]=CuBF4+ligands.[1]
Recently, we reported a new
enantioselective, direct synthe-
sis of the highly prized natural
which lead selectively to complex polycyclic compounds, are
generally catalyzed by platinum[4] or gold.[5] During further
studies on enynols of type C, we discovered that a cycliza-
tion–fragmentation pathway (Scheme 2, C to F) could com-
sandalwood odorant (À)-b-santalol (À)-5, which is based on
a
copper-catalyzed cyclization–fragmentation reaction
(Scheme 3).[7]
pete with the cyclopropanation, and that [Cu
ACHTUGNERTN(NUNG CH3CN)4]-
ACHTUNGTRENNUNG
Scheme 3. Synthesis of (À)-b-santalol ((À)-5) by cyclization–fragmenta-
tion of 3.[7]
Herein, we describe the copper(I)-catalyzed cycloisomeri-
zation of several 5-en-1-yn-3-ols and an exploratory exten-
sion to 6-en-1-yn-4-ols, which has led to the discovery of an
unprecedented metathesis fragmentation pathway and has
highlighted the complementary reactivity of the copper and
gold catalysts.
In a first attempt to generalize the [CuACHTUNGTRNEUNG(CH3CN)4]BF4-cat-
alyzed cyclopropanation with concomitant 1,2-H (or 1,2-
alkyl) shift (see 1 in Scheme 1),[1] we submitted the seco-
analogs 6 and 7[8] to the same reaction conditions. To our
surprise, both diastereomers 6 and 7 overwhelmingly led to
the rearranged dienones 8 and 9 (>94%), whereas the ex-
pected cyclopropanation/1,2-H shift reaction, which leads to
10, represented only a very minor pathway (0 to 6%;
Table 1). Evidently, the intermediate H (or its diastereomer)
can also undergo a Grob-type fragmentation, followed by
Scheme 2. Enynol cycloisomerization pathways. [M]=MXn+ligands (M=
Au, Pt, Cu).
[a] Dr. C. Fehr, Dr. M. Vuagnoux,+ Dr. H. Sommer
Firmenich SA, Corporate R&D Division
P. O. Box 239, 1211 Geneva 8 (Switzerland)
Fax : (+41)22-780-33-34
E-mail: charles.fehr@firmenich.com
cgfehr@bluewin.ch
À
protodemetalation and C C-double bond isomerization (see
[+] Postdoctoral fellow at Firmenich SA (July 2007–June 2008); Present
address: Syngenta Crop Protection, Route de lꢀIle au Bois, 1870
Monthey (Switzerland)
also Scheme 2). The cyclopropanation route was however fa-
vored to some extent by the use of PtCl2. Moreover, it re-
3832
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Chem. Eur. J. 2011, 17, 3832 – 3836

COMMUNICATION
Table 1. Cycloisomerization of 6 and 7.
Table 2. Cycloisomerization of 11.
Entry
1
Conditions[a]
GC yield [%]
12
13
14
7[b]
[Cu
(CH3CN)4]BF4
1
92
Cl(CH2)2Cl, 508C, 140 min
AHCTUNGTRENNUNG
Entry
Conditions[a]
GC yield [%]
Combined
yield [%][b]
2
PtCl2
Cl(CH2)2Cl, 508C, 3 h
33
5
62[c]
8
9
10
AHCTUNGTRENNUNG
6, [Cu
N
71
23
19
6
5
67
62
1
2
[a] [CuACHTUNRTGENUNG(CH3CN)4]BF4 (5 mol%); PtCl2 (5 mol%). [b] The epimer of 14
was formed (yield of 13: 60%). [c] Combined yield of 12, 13, and 14.
ClN(CH2)2Cl, 508C, 3 h
76[c]
6, PtCl2, Cl
508C, 1 h
N
30
17
0
53
<1
9
78
61
49
Apparently in this case the fragmentation pathway is dis-
favored as a result of the diminished strain in intermediate I
(Scheme 4). The ease of fragmentation could also be related
to the likelihood or not of E (Scheme 2) to undergo a 1,2-R-
shift (electrophilicity of the carbenoid and migration apti-
tude (H>CH3)). In addition, the use of the copper reagent
is supposed to favor the fragmentation pathway because it
leads to an intermediate of type D (Scheme 2), which has
more localized charges. The smaller size and marginal rela-
tivistic effects in copper as compared to gold (or platinum)
3
7, [Cu
N
>99
toluene, 508C, 24 h
4
7, PtCl2, Cl
508C, 24 h
N
76
15
[a] [CuACHTUNGTRENNUNG(CH3CN)4]BF4 (5 mol%); PtCl2 (5 mol%). [b] Combined yield of
8, 9, and 10. [c] Yields obtained in toluene, 508C, 5 h. [M]=MXn+li-
gands (M=Pt or Cu).
sulted that diastereomers 6 and
7 exhibit different selectivities
and reactivities (Table 1, en-
tries 1 and 2 vs. entries 3 and 4).
The ease of fragmentation
depends on the ability of the
À
C C bond to break and to
adopt a perpendicular arrange-
ment with respect to the plane
defined by the tertiary carbeni-
um-ion system (i.e., parallel to
the empty p orbital; see inter-
mediate H in Table 1; not possi-
ble in the example of
Scheme 1) and the amount of
Scheme 4. Cycloisomerization of 15 with chirality transfer. [a] Combined yield of 16 and 17. [M]=MXn+li-
gands (M=Cu, Pt, Ag).
accompanying strain release.
The same trends were ob-
served
with
enynol
11[9]
(Table 2). Whereas the copper(I)-catalyzed reaction mostly
afforded the cyclization–fragmentation product 13 (Table 2,
entry 1), PtCl2 favored the cyclopropanation route (62% of
14) and dienones 12 and 13 only represented 33 and 5%, re-
spectively, of the product mixture (Table 2, entry 2).
Compared with the tertiary alcohol 11, the secondary al-
cohol 15[2] showed a much higher propensity for the cyclo-
propanation pathway, but once again, copper catalysis
proved to be the most selective (25% of cyclization–frag-
might explain why cationic copper complexes are less effi-
cient in stabilizing an adjacent carbocation by backdonation
and likewise disfavor the formation of cyclopropylcarbenes
(Scheme 2).[10]
The copper-catalyzed reactions exhibit a remarkably high
degree of chirality transfer for both the cyclization–fragmen-
tation and the cyclopropanation reactions. The fact that 16
and 17 belong to the same enantiomeric series[11] and show
practically the same ee value is only possible if the two dia-
stereomeric intermediates I (I1 and I2 of unknown propor-
tion) evolve both to give 16 and 17 with a 3:1 selectivity.[2b]
The reactivity of 18[12] (Scheme 5), which contains a tri-
mentation in toluene; Scheme 4). [CuACHTUNRTGNE(UNG CH3CN)4]BF4 in 1,2-
dichloroethane gave mainly 16 in excellent yield and PtCl2
led exclusively to 16. AgNO3 exhibited surprisingly good re-
activity for the cyclopropanation reaction (16/17=89:11).
À
substituted C C double bond, is particularly interesting, as
intermediate J could in principle also undergo dehydration
Chem. Eur. J. 2011, 17, 3832 – 3836
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www.chemeurj.org
3833

C. Fehr et al.
Scheme 5. Cycloisomerization of 18. [a] ClCH2CH2Cl, 508C, 30 min.; combined yield of 19 and 20. [M]=MXn+ligands (M=Cu and Pt).
and aromatization, in close analogy to the findings of Bar-
riault and co-workers.[5c]
In the event, no dehydration product was detected and
the expected products 19 and 20 were formed exclusively.
Whereas CuI again greatly favored the cyclization–fragmen-
tation reaction, PtCl2 also afforded substantial amounts of
cyclopropanation product 20 (Scheme 5).
Finally, the sterically encumbered acyclic propargylic alco-
hol 21 gave rise exclusively to the cyclization–fragmentation
reaction, independent of the nature of the metal (Au, Pt, or
Cu; Scheme 6).[13]
Scheme 6. [a] CH2Cl2, 08C, 24 h. [b] Toluene, 708C, 4 h. [c] ClCH2CH2Cl,
708C, 210 min. [d] Combined yield of 22 and 23.
Scheme 7. [a] CH2Cl2,
08C,
1 h.
[b] CH2Cl2,
208C,
150 min.
As one of the prerequisites for successful fragmentation is
the formation of a carbenium ion in g-position towards the
OH group (regardless of the position of the acetylene), we
next explored the reactivity of 6-en-1-yn-4-ols such as
enynol 24[14] in the presence of Au, Pt, or Cu catalysts. Inter-
estingly, the fragmentation pathway was observed with each
catalyst used: after the initial 6-exo-dig cyclization, K under-
goes fragmentation to afford, after protodemetalation of L,
ketone 25 (Scheme 7, path a). In competition with the frag-
mentation pathway, K also evolved through the metathesis
pathway b; through M and N)[15] to give variable amounts of
the diene alcohol 26. The shown reaction pathways were fur-
ther corroborated by performing the reactions with the deu-
terated compound [D]24. This led to the expected products
[D]25 and [D]26.
[c] ClCH2CH2Cl, 508C, 75 min; + formation of 20% of an isomer of 26
(1,5-[H]-rearrangement product according to NMR). [d] ClCH2CH2Cl,
708C, 45 min. [e] Reaction performed on [H]24 and [D]24.
[PPh3AuCl]/Ag
ACHTUNGTRENNUNG
tion of 25, [CuACHTUNGTRENNUNG
[(tBuXPhos)AuNTf2][5d] largely favored the metathesis lead-
ing to 26, and PtCl2 showed intermediate selectivity. This ex-
ample demonstrates that the aforementioned reactions of 5-
en-1-yn-4-ols only in a formal sense represent enyne-Cope
rearrangements.[5b]
We next explored the reactivity of enynol 27[14] in the
presence of catalytic amounts of copper(I) or gold(I) cata-
lysts. As compared to 24, the olefin is part of a ring, and
therefore the metathesis reaction would give rise to a syn-
thetically very useful ring enlargement with concomitant
Subtle changes in the nature of the catalyst dramatically
change the outcome of the reaction. [(PPh3)AuNTf2][5d] and
3834
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Chem. Eur. J. 2011, 17, 3832 – 3836

Cyclization–Fragmentations of Enynols
COMMUNICATION
Scheme 8. a) [Cu
gands).
ACHTUNGTRENNUNG(CH3CN)4]BF4 (5 mol%), ClCH2CH2Cl, 708C, 3 h. b) [(PPh3)AuNTf2] (1 mol%), CH2Cl2, 08C, 1 h. [M]=CuBF4 or [AuNTf2] (+li-
(d), 158.1 (d), 160.0 (s), 199.2 ppm (s). MS: m/z (%): 206 [M]+ (21), 191
(58), 173 (18), 163 (42), 149 (27), 147 (36), 135 (65), 133 (47), 123 (81),
107 (78), 91 (54), 81 (44), 43 (100).
pentannulation.[16] This reaction mode was indeed followed
using [(PPh3)AuNTf2] (1 mol%), thus selectively affording
(through P and Q)[15] bicyclic alcohol 30 in 63% yield. On
Synthesis of 29: [CuACTHNUTRGNE(UNG CH3CN)4]BF4 (13.0 mg, 0.042 mmol) was added to a
the other hand, [CuACHTUNGTRENNUNG(CH3CN)4]BF4 (5 mol%) induced an un-
solution of 27 (200 mg, 92% pure; 0.836 mmol) in 1,2-dichloroethane
(5 mL) at RT under an atmosphere of nitrogen. The mixture was stirred
at 708C for 3 h. Standard work-up and chromatographic purification
(silica gel; cyclohexane/AcOEt 98:2) gave 29 (101.0 mg; 55%) as a color-
precedented metathesis fragmentation (probably through P
and R) that gave rise to the formation of 29. The absence of
the cyclization–fragmentation product 28 (through fragmen-
tation of O) may be due to the fact that intermediate O is
less strained than K (no gem-dimethyl group between C+
1
less oil. H NMR (400 MHz, CDCl3): d=1.09 (s, 3H), 1.52–1.56 (m, 4H),
1.64 (t, J=1.8 Hz, 3H), 2.17 (s, 3H), 2.30–2.39 (broad, 2H), 2.87–2.91
(broad, 2H), 3.13 (s, 2H), 4.72 (broad s,1H), 4.82 ppm (d, J=1.7 Hz,
1H). 13C NMR (100 MHz, CDCl3): d=21.7 (q), 23.7 (t), 29.2 (2q), 29.3
(q), 29.6 (t), 36.7 (t), 38.9 (s), 43.4 (t), 50.0 (t), 110.1 (t), 126.0 (s), 131.1
(s), 158.2 (s), 207.6 ppm (s). MS: m/z (%): 220 [M]+ (24), 205 (10), 187
(10), 177 (53), 162 (100), 147 (48), 121 (94), 107 (77), 93 (61), 91 (63), 43
(89).
À
and C OH) (see Scheme 7). Likewise, formal 5-exo-dig cyc-
lization of 27 would generate a spiro compound S which
cannot undergo fragmentation (Scheme 8). Based on
B3LYP/Lan12dz-calculations[17] only species P, formed in a
concerted manner, could be identified.
Synthesis of (Æ)-30:
A cooled (08C) solution of [(PPh3)AuNTf2]
In conclusion, we have demonstrated that [Cu
ACHTUGNERTN(NUNG CH3CN)4]-
(13.0 mg, 8.28 mmol) in CH2Cl2 (3 mL) was treated with 27 (200 mg, 92%
pure; 0.836 mmol) and stirred for 1 h. Standard work-up and chromato-
graphic purification (silica gel; cyclohexane/AcOEt 98:2) gave 30
(116.0 mg; 63%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=0.88
(s, 3H), 1.01 (s, 3H), 1.41 (s, 3H), 1.46–1.54 (m, 1H), 1.65 (split s, 3H),
1.69–1.78 (m, 1H), 1.78–1.86 (m, 2H), 1.93–2.02 (m, 1H), 2.14 (dt, J=
10.7, 2.8 Hz, 1H), 2.35–2.46 (m, 2H), 2.45 (split d, J=16.4 Hz, 1H), 2.61
(split d, J=16.4 Hz, 1H), 5.77 ppm (broad s, 1H; NOE with 1.98, but not
with 1.65). 13C NMR (100 MHz, CDCl3): d=19.5 (q), 23.0 (q), 27.5 (t),
28.6 (q), 34.4 (q), 37.7 (s), 39.7 (t), 42.8 (t), 49.8 (t), 51.4 (t), 77.8 (s),
121.5 (d), 133.1 (s), 145.3 (s), 147.1 ppm (s). MS: m/z (%): 220 [M]+ (14),
205 (25), 202 (13), 187 (40), 177 (18), 159 (100), 147 (73), 119 (73), 105
(43), 91 (47), 43 (58).
ACHTUNGTRENNUNG(BF4) effectively catalyzes the cyclization–fragmentation of
5-en-1-yn-3-ols and have unveiled new fragmentation and
metathesis reactions of 6-en-1-yn-4-ols. Further applications
of these new reactions are currently under active investiga-
tion.
Experimental Section
Synthesis of (Æ)-13: [Cu
ACHTNUGRTNE(NUGN CH3CN)4]BF4 (18.2 mg, 0.058 mmol) was added
to a solution of 11 (220 mg, 1.07 mmol) in 1,2-dichloroethane (5 mL) at
RT under and atmosphere of nitrogen. The mixture was stirred at 508C
for 140 min. The dark-gray mixture was cooled at RT, filtered through a
short pad of silica gel and concentrated under reduced pressure. The
orange-colored oil (201 mg; 12/13/14=1:92:7)) was purified by chroma-
tography (silica gel; cyclohexane/AcOEt 95:5) to afford 13 (133.0 mg;
60%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d=1.01 (s, 3H),
1.14 (s, 3H), 1.21 (s, 3H), 1.32–1.75 (m, 5H), 1.83–1.92 (m, 1H), 2.26 (s,
3H), 4.93 (s, 1H), 5.06 (s, 1H), 6.07 (d, J=16.5 Hz, 1H), 6.82 ppm (d, J=
16.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): d=18.8 (t), 26.9 (q), 29.4
(q), 29.8 (q), 31.5 (q), 36.8 (s), 38.1 (t), 41.0 (t), 42.8 (s), 108.8 (t), 127.6
Acknowledgements
We thank Professor M. Santelli (University of Aix-Marseille, France) for
the calculations and stimulating discussions.
Keywords: copper · cycloisomerization · fragmentation ·
gold · rearrangement
Chem. Eur. J. 2011, 17, 3832 – 3836
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www.chemeurj.org
3835

C. Fehr et al.
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[8] Compounds 6 and 7 were obtained from the corresponding aldehyde
(HCCMgBr (1.2 equiv), THF, RT (72%; 6/7=4:1). For determina-
tion of the configuration,
6 was transformed in three steps
a) mCPBA (1.3 equiv), CH2Cl2, 08C to RT (93%; 64:36); b) major
diast.+PhSLi (0.95 equiv), À788C
to RT (78% conv.; 56%); c) 2-
methoxypropene
(10 equiv),
CF3CO2H (0.75 equiv), DMF, RT
(52%)) into the rigid 1,3-dioxane
a, whose structure could be un-
ambiguously assigned by NOE
between the angular CH3, the an-
gular CH2SPh and the propargylic
H.
[9] Compund 11 was obtained from the corresponding ketone
(HCCMgBr (2.2 equiv), CeCl3 (1.2 equiv), LiCl (1.2 equiv), THF,
RT (89%).
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a) NaClO2 (1.15 equiv), iso
H2O, 45 8C, 2 h; b) Me2NCH
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
30 min, separation on chiral capillary column (CP-Chirasil-DEX CB
(25 m ꢅ 0.25 mm) (Chrompack)): second peak major; c) Raney-Ni-
AHCTUNGTRENNUNG
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(1.3 equiv), CH2Cl2, RT, 97%; 3) HCCMgBr (1.2 equiv), THF, RT
(53%+starting ketone (25%)).
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Z=4:1) in 43% yield and the use of [CuACTHNUTRGNE(UNG CH3CN)4]BF4 under other-
wise identical conditions gave only 14% of rearranged product and
64% of starting material.
[14] Compounds 24 and 27 were prepared by addition of the correspond-
ing methyl ketones to propargylmagnesium bromide (1.5 equiv) in
THF in 91 and 47% yield, respectively.
À
À
[15] Migration of the cyclopropane C C bond opposite to the C C=M
bond in M (Scheme 7) and P (Scheme 8) leads to the same metathe-
sis product. These reactions proceed via non-classical cations, but
for clarity we prefer not to draw partial bonds.
[16] For a related early study of platinum-catalyzed metathesis reactions
leading to bridged bicyclic systems: A. Fꢃrstner, F. Stelzer, H. Szil-
lat, J. Am. Chem. Soc. 2001, 123, 11863; A. Fꢃrstner, H. Szillat, B.
Gabor, R. Mynott, J. Am. Chem. Soc. 1998, 120, 8305.
[17] Kindly performed by Professor M. Santelli (University of Aix-Mar-
seille, France).
Received: August 12, 2010
Revised: January 13, 2011
Published online: March 4, 2011
3836
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