Gold-catalyzed cycloisomerization of 1,6-diyne carbonates and esters to 2,4a-dihydro-1 H-fluorenes

Article abstract of DOI:10.1021/ja4032727

A synthetic method to prepare 2,4a-dihydro-1H-fluorenes efficiently from gold(I)-catalyzed 1,2-acyloxy migration/cyclopropenation/Nazarov cyclization of 1,6-diyne carbonates and esters is described. The suggested reaction pathway provides rare examples of [2,3]-sigmatropic rearrangement in this class of compounds as well as the involvement of an in situ formed cyclopropene intermediate in gold catalysis. Experimental and ONIOM(QM:QM′) [our own n-layered integrated molecular orbital and molecular mechanics(quantum mechanics:quantum mechanics′)] computational studies based on the proposed Au carbenoid species provide insight into this unique selectivity.

Full text of DOI:10.1021/ja4032727

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Article
Gold-Catalyzed Cycloisomerization of 1,6-Diyne
Carbonates and Esters to 2,4a-Dihydro-1H-fluorenes
Weidong Rao, Ming Joo Koh, Dan Li, Hajime Hirao, and Philip Wai Hong Chan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4032727 • Publication Date (Web): 29 Apr 2013
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Journal of the American Chemical Society
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Gold-Catalyzed Cycloisomerization of 1,6-Diyne Carbonates
and Esters to 2,4a-Dihydro-1H-fluorenes
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Weidong Rao, Ming Joo Koh,† Dan Li,† Hajime Hirao* and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore
Supporting Information Placeholder
ABSTRACT: A synthetic method to prepare 2,4a-dihydro-1H-fluorenes efficiently from gold(I)-catalyzed 1,2-acyloxy migra-
tion/cyclopropenation/Nazarov cyclization of 1,6-diyne carbonates and esters is described. The suggested reaction pathway pro-
vides rare examples of [2,3]-sigmatropic rearrangement in this class of compounds as well as the involvement of an in situ formed
cyclopropene intermediate in gold catalysis. Experimental and ONIOM(QM:QM’) (our own n-layered integrated molecular orbital
and molecular mechanics(quantum mechanics:quantum mechanics’)) computational studies based on the proposed Au carbenoid
species provide insight into this unique selectivity.
Scheme 1. Gold-Catalyzed Reactivities of 1,n-Diyne Carbonates
and Esters
INTRODUCTION
1,n-Diyne cycloisomerizations catalyzed by mono- and triva-
( )n
OCOR1
[Au]+
( )n
OCOR1
[Au]+
( )n
lent complexes of gold have emerged as one of the most effi-
cient and atom-economical strategies for complex molecule
synthesis in a single step.1-3 Included in this rapidly expanding
field have been an increasing number of elegant methods to
prepare synthetically useful cyclic compounds from 1,n-diyne
carbonates and esters 1 shown in Scheme 1.3 The reactions
typically involve the allenyl intermediate II arising from the
propensity of the acyloxy moiety of the gold-activated sub-
strate I to undergo 1,3-migration (Scheme 1, eq 1, path a). The
only notable exception to this mode of reactivity is the Au(I)-
catalyzed concerted 5-endo-dig/7-endo-dig cyclization of syn-
1,7-diyne benzoates to indeno[1,2-c]azepines via the gold-
coordinated adduct VI (Scheme 1, eq 2).3a In contrast, the ana-
logous transformations of 1,n-diyne esters initiated by a 1,2-
acyloxy shift, thereby providing access to a potentially wider
scope of cycloisomerization products, have so far remained
unrealized. With this in mind and as part of studies examining
the utility of gold catalysis in organic synthesis,4 we became
interested in the cycloisomerization chemistry of 1,6-diyne
carbonates and esters 1 (Scheme 1, eq 1, path b). It was antic-
ipated that such substrates containing a sterically less hindered
terminal carbonate or estereal C≡C bond might be more prone
to 1,2-acyloxy migration and subsequent trapping of the en-
suing gold carbenoid adduct III by the remaining alkyne
moiety. Cycloreversion of the resulting cyclopropene interme-
diate IV, the formation of which in gold catalysis is extremely
rare, to give the gold carbenoid species V followed by Nara-
zov cyclization would then be expected to provide 2,4a-
dihydro-1H-fluorene derivatives.5-8 Herein, we report the de-
tails of this chemistry that offers an expedient and chemose-
lective approach to this carbocyclic motif, present in many
bioactive natural and synthetic compounds and functional
materials,9 in good to excellent yields. An ONIOM computa-
tional study on the origin of the observed selectivity was also
performed employing two different levels of quantum me-
chanical methods (ONIOM(QM:QM’)).10
refs 1,3
OCOR1
path a
[Au]+
products
R3
R2 R3
R2 R3
R2
1
I
II
R2
=
(1)
path b
R3 = H, n = 1
OCOR1
OCOR1
OCOR1
[Au]+
[Au]+
this work:
−[Au]+
[Au]+
III
IV
V
−[Au]+
OCOR1
2
R2
R2
R2
[Au]+
ref 3a
BzO
R1
BzO
R1
(2)
BzO
R1
N
N
Ts
N
Ts
Ts
[Au]+
VI
RESULTS AND DISCUSSION
We began our investigations by examining the gold-
catalyzed cycloisomerizations of 1,6-diyne ester 1a to estab-
lish the reaction conditions (Table 1).11 This initially revealed
that treating 1a with 5 mol % of Au(I) catalyst A in dichloro-
methane at room temperature for 6 h afforded 2a in 71% yield
(entry 1). The structure of the 2,4a-dihydro-1H-fluorene prod-
1
uct was determined by H NMR spectroscopic measurements
and X-ray crystallography (Figure 1).12 Our studies subse-
quently showed that when the reaction was repeated with the
more sterically crowded gold(I) complex C in place of A as
the catalyst, the product yield increased from 71 to 78% (entry
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3).13 In contrast, replacing A with the Au(I) phosphine com-
Page 2 of 8
1
plexes B and D−F, NHC-gold(I) (NHC = N-heterocyclic car-
bene) complex G, and gold(I) phosphite complex I as the cata-
lyst was found to result in lower product yields of 12-67%
(entries 2, 4−6, 9 and 11).14 In the case of the reactions me-
diated by Au(I) phoshine complexes E and F, the substrate
was also recovered in 70 and 50% yield, respectively (entries
5 and 6). With Au(I) phoshine complex C as the catalyst, a
similar outcome was found with 2a obtained in 27% yield on
changing the reaction medium from dichloromethane to tolu-
ene (entry 13). In contrast, no reaction was detected in control
experiments mediated by PPhAuCl, AuCl, NHC-gold(I) com-
plex H or gold(III) complex K, or Au(I) complex C in polar
solvents such as acetonitrile and THF (entries 7, 8, 10, 12, 14
and 15). On the basis of the above results, the reaction of 1a in
the presence of Au(I) complex C (5 mol %) as catalyst in dich-
loromethane at room temperature for 6 h provided the opti-
mum conditions.
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Figure 1. ORTEP Drawing of 2a with Thermal Ellipsoids at 50%
Probability Levels12
Table 1. Optimization of the Reaction Conditionsa
proved to be broad and a variety of substituted 2,4a-dihydro-
1H-fluorenes could be furnished in 44−93% yield from the
corresponding substrates 1b−y. Reactions of substrates con-
taining a Bz (1b), Ac (1c), Cbz (1d) or Boc (1e) instead of a
PNB migrating group were found to be well tolerated under
the reaction conditions and furnished 2b−e in 52−80% yield.
OPNB
OPNB
Ph
[Au]+ (5 mol%)
Ph
solvent, rt
6 h
Ph
2a
1a
R1 R1
1 R1
R
SbF6
SbF6
Table 2. Cycloisomerization of 1,6-Diyne Carbonates and Esters
R3
R4
P
Au NCMe
Ar
N
N
Ar
P
AuNTf2
1b-y Catalyzed by Ca
R2
R2
R4
R2
Au
L
R2
R2
OR1
R2
R2 OR1
R3
R2
C (5 mol%)
A: R1 = tBu, R2 = R3 = R4 = H
G: Ar = 2,6-iPr2C6H3,
L = PhCN
H: Ar = 2,6-iPr2C6H3,
L = DMAP
E: R1 = tBu, R2 = H
F: R1 = Cy, R2 = iPr
B: R1 = Cy, R2 = iPr, R3 = R4 = H
C: R1 = tBu, R2 = iPr, R3 = R4 = Me
D: R1 = Cy, R2 = iPr, R3 = OMe, R4 = H
5
CH2Cl2, rt
2−24 h
R3
R4
R3 R4
1
2
tBu
OR
O
O
N
SbF6
2f: R = Me (83%)
Ph
tBu
O
P Au-NCPh
3
Cl Au
Cl
R
2g: R = OMe (71%)
2h: R = nPent (81%)
2i: R = Ph (77%)
2j: R = vinyl (47%)
2k: R = F (64%)
OBz
I
J
Ph
2b: R = Bz (80%)
2c: R = Ac (71%)
2d: R = Cbz (55%)
2e: R = Boc (52%)
entry
catalyst
solvent
CH2Cl2
yield (%)b
2l: R = Br (55%)
1
2
3
4
5
6
7
8
9
71
67
78
A
B
C
D
E
F
R
R
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
Me
OBz
S
OBz
OBz
Ph
Me
Ph
Ph
52
12(70)c
38(50)c
Me
2m: R = H (80%)
2n: R = Me (77%)
2o: (83 %)
2p: (72%)
d
Ph3PAuCl
-
OMe
d
AuCl
G
H
I
-
OBz
62
OBz
d
Ph
10
11
12
13
14
15
-
Ph
O
O
50
Ph
Ph
d
-
J
C
C
C
27
d
2q: (77%)
2r: (71%)
2s: (57%)
MeCN
THF
-
d
OBz
R
-
OBz
OBz
a
R
All reactions were performed at the 0.2 mmol scale with
catalyst:1a ratio = 1:20 in given solvent at room temperature for
6 h. PNB = p-nitrobenzoyl. b Isolated yield. c Reaction carried out
at room temperature for 24 h; values in parentheses denote the
Me Me
2w: R = H (47%)c
2x: R = OMe (44%)c
2y: (93%)c
2t: R = 4-ClC6H4 (76%)
2u: R = 4-vinylC6H4 (60%)
2v: R = 1-naphthalenyl (53%)b
d
yield of recovered starting material. No reaction based on TLC
and 1H NMR analysis of the crude mixture.
a All reactions were performed at the 0.2 mmol scale with C:1 ra-
tio = 1:20 in CH2Cl2 at room temperature for 2−24 h. Values in
parentheses denote isolated product yields. b Isolated as an insepar-
The scope of the present procedure was next assessed with a
series of 1,6-diyne carbonates and esters, and the results are
summarized in Table 2. In general, these experiments showed
that with Au(I) complex C as catalyst, the reaction conditions
c
able mixture of diastereomers in a ratio = 1.1:1. Reaction carried
out with NHC-gold(I) complex G as the catalyst.
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posited participation of the gold carbenoid intermediate V
Likewise, starting 1,6-diyne esters with a pendant aryl (1f−o
1
shown in Scheme 1, eq 1, is supported by our findings when
the reactions of 1a were repeated with cyclohexene and Ph2SO
catalyzed by NHC-gold(I) complex G under the standard con-
ditions (Scheme 2, eq 2 and 3).17,18 In both test reactions, the
production of the anticipated trapping products, the cyclopro-
pane and ketone adducts 3a and 4a, was achieved in respective
yields of 71 and 80%.13 In a final control experiment, the ori-
gin of the proton source in the protodeauration process leading
to product formation was also shown to likely come from the
regeneration of aromaticity or alkene bond in the Nazarov
cyclization step.7 Under the standard conditions depicted in
Scheme 2, eq 4, subjecting d5-1b to the gold(I) catalyst C was
found to give d5-2b in 75% yield and with a D content of 80%
and 1q−r), thiophene (1p) or cyclohexene (1s) functional
group at the alkyne carbon center were found to proceed to
give the corresponding tri-, tetra- and pentacyclic adducts in
47−83% yield. The presence of other aryl motifs on the ben-
zoate carbon center of the starting material (1t−v) was found
to have little influence on the course of the reaction with 2t−v
furnished in 53−76% yield. The reactions of substrates con-
taining a cyclopropane ring on the benzoate carbon center (1w
and 1x) or methyl groups at the C5 position (1y) were ob-
served to be the only exception. In these experiments, while
the use of either gold(I) catalysts C or G as the Au(I) catalyst
gave similar product yields, the latter was found to form less
impurities that were easier to remove by flash column chroma-
tography. More notably, all the above examined cycloisomeri-
zations also demonstrated that the ring-forming process occurs
in a highly selective manner with the 1,4-diene isomer of the
adduct only being furnished. Added to this, other than a num-
ber of unidentifiable decomposition products, no other cyclic
adducts that could be formed from an initial 1,3-acyloxy mi-
gration step or concerted double cyclization pathway were
detected by 1H NMR analysis of the crude mixtures.
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1
at the C9 position of the adduct, as determined by H NMR
measurements.
A tentative mechanism for the present gold(I)-catalyzed
2,4a-dihydro-1H-fluorene forming reaction is outlined in
Scheme 3. Using 1b as a representative example, this might
initially involve activation of the estereal alkyne moiety of the
substrate by the Au(I) catalyst to give the gold(I)-coordinated
complex Ib. This results in syn 1,2-migration of the carbox-
ylate functional group to produce gold carbenoid adduct IIIb
via 1,3-dioxin-1-ium intermediate VIIb. Trapping of this new-
ly formed organogold species by the remaining C≡C bond
may then provide the putative cyclopropene adduct IVb.6 Fur-
ther coordination of the π-acidic metal complex to the alkene
bond of the bicyclic intermediate might next provide the
gold(I)-activated species VIIIb. Subsequent electrophilic ring-
opening of the cyclopropenyl gold moiety in VIIIb would
give the second gold carbenoid adduct Vb and its gold-
stabilized allylic carbocation isomer Vb’. This is the active
species that undergoes Nazarov cyclization,7 which upon re-
aromatization of the ensuing Wheland-type intermediate IXb
followed by protodeauration, would regenerate the gold(I)
catalyst and deliver 2b.
To provide further support as well as to gain a better under-
standing of the mechanistic premise put forward in Scheme 1,
the following control experiments were performed (Scheme
2). In view of recent works showing the likely involvement of
Au(I)-activated alkynylgold(I) species in alkyne cycloisomeri-
zations mediated by the metal catalyst,15 we first examined the
reaction of d1-1a in dichloromethane with 5 mol % of gold(I)
complex C under the conditions described in Scheme 2, eq 1.
This gave d1-2a in 75% yield and with a D content of 94%,
1
based on H NMR measurements, that led us to rule out the
possible involvement of a dual activation pathway in which
the alkyne terminus of 1 was activated by two molecules of
the Au(I) catalyst. This was further supported by conducting
the reaction again for a second time in the presence of an
equimolar amount of 1l and obtaining d1-2a and 2l as the only
products in 60 and 65% yield, respectively, based on 1H NMR
analysis of the crude reaction mixture.16 On the other hand, the
Scheme 3. Proposed Mechanism for Au(I)-Catalyzed Cycloisome-
rization of 1,6-Diyne Carbonates and Esters Represented by 1b
Ph
Ph
Ph
O
Scheme 2. Control Experiments with 1a, d1-1a and d5-1b Cata-
lyzed by C or G
[Au]+
Ph
Ph
O
O
Ph
1b
OBz
[Au]+
O
[Au]+
Ib
[Au]
VIIb
OPNB
D
Ph
Ph
PNBO
Ph
C (5 mol%)
D
Ph
(1)
IIIb
CH2Cl2, rt, 6 h
Ph
−[Au]+
d1-1a
d1-2a
OBz
OBz
Ph
OBz
94% D-content
Ph
75% yield, 94% D-content
Ph
Ph
OBz
[Au]+
Ph
cyclohexene PNBO
(50 eq)
H
H
Ph
(2)
(3)
[Au]+
VIIIb
Ph
Ph
[Au]+
[Au]
Vb'
Vb
IVb
G (5 mol%)
CH2Cl2, rt, 6 h
3a
71% yield
1a
Ph2SO
(5 eq)
PNBO
Ph
O
H+ tra-
nsfer
BzO
H
Ph
2b
Ph
4a
80% yield
−[Au]+
[Au]
D
OBz
Ph
D
IXb
OBz
D
D
D
C (5 mol%)
D
Ph
To further verify our proposed mechanism shown in
(4)
D
Scheme 3, we undertook two-layer ONIOM(QM:QM’)10 com-
putational studies using Gaussian 09.19 The B3LYP functional
was used for both QM layers,20 in combination with three dif-
ferent basis sets, i.e. LANL2MB (B1), [SDD(for Au),6-
CH2Cl2, rt, 2 h
D
9
D
D
d5-2b
d5-1b
100% D-content
75% yield, 80% D-content
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Page 4 of 8
31G*(for others)] (B2), and [LANL2TZ(f)(for Au),6-
311+G(d,p)(for others)] (B3).21-23 Geometry optimizations and
frequency calculations were performed at the
ONIOM(B3LYP/B2:B3LYP/B1) level, and single-point ener-
gy calculations were done on optimized geometries at the
ONIOM(B3LYP/B3:B3LYP/B1) level; for the latter, the dich-
loromethane solvent effect was taken into account with the
IEFPCM (integral equation formalism variant of the polariza-
ble continuum model) method.24 UCSF Chimera was used to
draw the molecules.25 The ONIOM calculations produced a
1
2
3
4
5
6
7
8
number of transition states and intermediates on the reaction
pathway from 1b to 2b. Full geometric and energetic data are
summarized in the SI, and key results are presented here (Fig-
ure 2). Our calculations show that an intermediate with a six-
membered ring (Int3) is easily formed between IIIb and
VIIIb via a transition state for ring closure (TS3). A particu-
larly interesting feature of our delineated mechanism is that
Int3 undergoes another ring closure to generate a unique
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Figure 2. Reaction energy diagram (in kcal/mol) for the middle stage of the reaction, as obtained at the ONIOM(B3LYP/B3:B3LYP/B1)-
PCM//ONIOM(B3LYP/B2:B3LYP/B1) level with zero-point energy corrections.10 An alternative pathway between Int3 and Int5 via
TS4b is indicated by a dotted line. In the 3-D figures, H, C, O, P, and Au atoms are colored white, grey, red, orange, and gold, respective-
ly. The ball-and-stick representation is used for the high-level QM layer and the stick representation is used for the rest of the system.
Schematic drawings of the transition states along with Int3 and Int5 are also given below the energy diagram. Relative energy values are
given with respect to the energy of isolated 1b and [AuL(NCCH3)]+ from catalyst C.
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cyclopropene adduct Int4 (VIIIb in Scheme 3) via TS4a with plates. Low resolution mass spectra were determined on a
1
2
3
4
5
6
7
8
an energy barrier of 11.1 kcal/mol. This is followed by a cyc-
lopropene ring-opening process through TS5 that has an ener-
gy barrier of 11.3 kcal/mol. As such, this implied that, despite
its transient formation, the relative ease in which the cyclopro-
pene intermediate can undergo ring-opening makes it unlikely
that the putative cyclic adduct can be trapped experimentally.
Our calculations further suggest that there is an alternative
pathway from Int3 to Int5 via TS4b that involves gold migra-
tion, as shown in Figure 2. As can be seen from the structure
of TS4b, this transition state features the geometry of a four-
membered ring that allows efficient 1,3-migration of the gold
catalyst. However, TS4b turns out to be slightly higher in
energy than TS4a, and thus, this alternative Au migration
pathway should be slightly less favorable than that involving
cyclopropene formation via TS4a. During the reaction, Naza-
rov cyclization of Int6 to Int7 has the highest energy barrier
(22.1 kcal/mol), suggesting that the prior intermediates (Int5
and Int6 (Vb in Scheme 3)) should be relatively long-lived.
For the reaction steps after the formation of Wheland-type
intermediate Int7 (IXb in Scheme 3), the benzoyl group was
found to play a pivotal role in assisting the 1,3-proton migra-
tion by accepting and donating the proton appropriately to
yield the final product (see Figure S2 in the SI). These calcu-
lated results are also consistent with the experimentally ob-
served preferential formation of 3a and 4a and the high D con-
tent found at the C9 position of d5-2b as reported in Scheme 2,
eq 2−4.
mass spectrometer and reported in units of mass to charge ratio
(m/z). High resolution mass spectra (HRMS) were obtained on
a LC/HRMS TOF spectrometer using simultaneous electro-
spray (ESI).
General Procedure for Gold Complex C Catalyzed Cycloi-
somerization of 1,6-Diyne Carbonates and Esters 1 to 2,4a-
Dihydro-1H-fluorene Derivatives 2. To a solution of 1,6-
diyne carbonate or ester 1 (0.2 mmol) in anhydrous CH2Cl2 (4
mL) was added gold(I) complex C (10 μmol). The reaction
mixture was stirred at room temperature for 2−24 h until TLC
analysis indicated that the reaction was complete. The reaction
mixture was then concentrated under reduced pressure and
purified by flash column chromatography on silica gel (eluent:
nhexane:EtOAc:CH2Cl2 = 50:1:1) to give the title compound.
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General Procedure for Control Reactions of 1a with Cyclo-
hexene and Diphenyl Sulfoxide Catalyzed by Gold Com-
plex G. To a 2 mL CH2Cl2 solution containing gold(I) complex
G (10 μmol), cyclohexene (10 mmol) or diphenyl sulfoxide
(1.0 mmol) was added a solution of 1a (0.2 mmol) in CH2Cl2
(3 mL). The reaction mixture was stirred at room temperature
for 6 h until TLC analysis indicated that the reaction was com-
plete. The reaction mixture was then concentrated under re-
duced pressure and purified by flash column chromatography
on silica gel (eluent: nhexane:EtOAc:CH2Cl2 = 50:1:1) to give
the product 3a or 4a, respectively.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, characteriza-
tion data, crystal structure data (CIF), raw ONIOM data, XYZ
coordinates, and complete ref 18. This material is available free of
charge via the Internet at http://pubs.acs.org.
CONCLUSIONS
In summary, we have developed a gold(I)-catalyzed strategy
for the construction of highly functionalized 2,4a-dihydro-1H-
fluorenes from the respective 1,6-diyne carbonates and esters.
Our studies suggest that the tandem process was initiated by a
1,2-acyloxy migration step previously not seen in this class of
substrates. It also hints at the possible involvement of an in situ
formed cyclopropene intermediate, examples of which have
remained conspicuously rare in gold catalysis. Exploration of
the scope and synthetic applications of the present reactions
are in progress and will be reported in due course.
AUTHOR INFORMATION
Corresponding Authors
waihong@ntu.edu.sg (P.W.H.C.), hirao@ntu.edu.sg (H.H.)
Author Contributions
† These authors contributed equally to this work.
EXPERIMENTAL SECTION
ACKNOWLEDGMENT
This work was supported by College of Science Start-Up Grants
(to P.W.H.C. and H.H.) from Nanyang Technological University
(NTU) and a Science and Engineering Research Council Grant
(092 101 0053, to P.W.H.C.) from A*STAR, Singapore. An Un-
dergraduate Research Experience on Campus stipend (to M.J.K.)
from NTU is also gratefully acknowledged. We thank Dr. Yong-
xin Li of this Division for providing the X-ray crystallographic
data reported in this work and the High Performance Computing
Centre at NTU for computing resources.
General Considerations. All reactions were performed in
oven-dried glassware under an argon atmosphere. Unless spe-
cified, all reagents and starting materials were purchased from
commercial sources and used as received. Compound 1 was
prepared following literature procedures.11 Gold complexes
A−J were purchased from commercial sources or prepared
following literature procedures.11 Solvents were purified fol-
lowing standard literature procedures. Analytical thin layer
chromatography (TLC) was performed using pre-coated silica
gel plate. Visualization was achieved by UV light (254 nm).
Flash chromatography was performed using silica gel and gra-
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1
2
TOC
O
O
[Au]+
=
3
4
5
6
O
tBu tBu
Au NCMe
R2
R1
SbF6
[Au]+ (5 mol%)
Me
Me
P
O
R2
iPr
R1
Me
iPr
CH2Cl2, rt
2-24 h
iPr
Me
25 examples
44-93% yield
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