Alternation of chemoselective control in Stille-Heck and Heck-Stille reaction sequences

Article abstract of DOI:10.1002/adsc.200800678

Sequential and one-pot Stille-Heck and Heck-Stille reaction processes have been invoked to give divergent access to polycyclic ring systems. Both reaction conditions and substrate structure are important in determining the nature of the reaction products

Full text of DOI:10.1002/adsc.200800678

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DOI: 10.1002/adsc.200800678
Alternation of Chemoselective Control in Stille–Heck and Heck–
Stille Reaction Sequences
Kye-Simeon Mastersa and Bernard L. Flynna,*
a
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal
Parade, Parkville, Victoria 3052, Australia
Fax : (+61)-3-9903-9582; e-mail: bernard.flynn@vcp.monash.edu.au
Received: November 3, 2008; Published online: February 13, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800678.
Abstract: Sequential and one-pot Stille–Heck and
Heck–Stille reaction processes have been invoked
to give divergent access to polycyclic ring systems.
Both reaction conditions and substrate structure are
important in determining the nature of the reaction
products formed. The Heck–Stille reactions have in-
volved a reversal of the usual Heck regioselectivity
and both cine- and ipso-substitutions have been ob-
served in the Stille reaction.
Keywords: Heck reaction; one-pot process; palladi-
um coupling; Stille reaction
In recent years, de Meijere and co-workers have dem-
onstrated the utility of 2-bromoalkenyl trifluorome-
thanesulfonates 1 as substrates in sequential palladi-
um-mediated reaction processes.[1] For example,
Stille–Heck reaction sequences can be conducted in
Scheme 1. Stille and Heck reaction sequences.
one-pot, where 1 reacts with a vinylstannane selec-
tively at the triflate to give 2, then with a Heck ac-
ceptor at the bromide to give a 1,3,5-hexatriene 3 of regioselectivity of the annulated product (condi-
(Scheme 1). Conjugated hexatrienes 3 can then be tional control). In this preliminary report we describe
converted to 6-membered rings 4 by 6p-electrocyclisa- how reaction conditions can be manipulated to
tion. In building on this methodology, we were inter- achieve either outcome, Stille–Heck or Heck–Stille, in
ested in linking the organostannane of the Stille reac- a highly selective manner.[2]
tion to the alkene of the Heck reaction with a tether,
For the purpose of this study we prepared 2-bro-
as in 5. Palladium-catalysed reaction of 1 with 5 can mo(and chloro)-3,4-dihydronaphthalenyl triflates 10
then give cyclic structures 6 and 7 directly via a and 11 from the known 2-bromo- (and chloro-)tetra-
Stille–Heck or Heck–Stille process, respectively. lones 8[3] and 9,[4] respectively (Scheme 2). The 2-halo-
Unlike the one-pot, three-component process devel- tetralone was deprotonated with KHMDS in THF at
oped by de Meijere and co-workers, where the order À788C, then treated with N-2-pyridyltriflimide.[2] It
of addition of the Stille and Heck substrates deter- was found that further addition of triflic anhydride to
mines the regioselectivity of their incorporation into the reaction mixture after 2 h resulted in a higher
the product (temporal control), tethering the Stille yield of triflate than with either reagent by itself.[5]
and Heck substrates means that the relative rates of
Two Stille–Heck “acceptor” compounds 16 and 17
the two reactions will determine the nature and level were prepared from readily available (12) and 2-
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Alternation of Chemoselective Control in Stille–Heck and Heck–Stille Reaction
COMMUNICATIONS
time did not assist in converting 22 to 21 under these
conditions. Nonetheless, we were able to convert 22
to 21 in a separate step using the more reactive cata-
lyst Pd(0)ACHTUNGTRENGN(U t-Bu3P)2 and Cs2CO3 in NMP at 908C for
7 h, giving 21a/b in good yield (67%; Scheme 5).[2]
We next turned to see if the chemoselectivity of
this process could be reversed, such that the Heck
preceeds the Stille reaction (Heck–Stille reaction). By
reacting 11 and 16 under typical Heck conditions, pal-
Scheme 2. Synthesis of 1,2-diactivated alkenes.
(buten-4-yl)-1,3-cyclahexadione (13), respectively.[2,6] ladium tetrakistriphenylphosphine with dry NaOAc in
Diones 12 and 13 were converted to bromoenones 14 1,2-dichloroethane (DCE) at 808C (Conditions B), we
and 15, by treatment with Ph3P.Br2.[2,6] These were in were able to isolate the Heck product 23 in good
turn converted to the alkenylstannanes 16 and 17 yield (72%), with excellent regioselectivity. Interest-
upon reaction with Me3SnCu·LiCN in THF/ ingly, the regioselectivity of this reaction is the oppo-
HMPA.[2,7]
site to that expected for a Heck reaction involving an
For a regioselective, one-pot Stille–Heck reaction alkenyl triflate and terminal olefin in the absence of a
we employed a combination of Pd
(dba)2, tri-(2-furyl)- bidendate ligand.[8] In a one-pot Heck–Stille process,
AHCTUNGTRENNUNG
phosphine (TFP) and copper(I) thiophene carboxyl- Conditions B were again employed until completion
ate (CuTC) co-catalyst with LiCl and K2CO3 as addi- of the Heck reaction, the DCE was then evaporated
tives, the latter was added to ensure continual cycling and LiCl, CuTC, additional palladium catalyst and
of the catalyst in the intramolecular Heck reaction of NMP (solvent) were added (Conditions C), and the
intermediate 18 (Conditions A). When the reaction of mixture further heated to give the unexpected spiro-
11 and 16 under Conditions A was heated at 558C for cycle 24 in reasonable overall yield (51% from 11).
4 h the Stille product 18 was the only product isolated The same product was isolated in an 81% yield when
(75%). However, heating at 858C for 3 h gave the an- the Stille reaction was performed directly on isolated
nulated Stille–Heck product 19, with in situ aromati- 23 (Conditions D). Compound 24 appears to have re-
sation, in reasonable yield (54% from 11).
sulted from unprecedented intramolecular cine-substi-
Also, when 11 and 17 were subjected to Conditions tution of the stannane.[9] Remarkably, the Heck–Stille
A at 858C for 4 h the Stille–Heck product 21a/b (mix- product, compound 24, has resulted from two palladi-
ture of double bond isomers 1:2) was obtained in um-mediated processes with unusual regioselectivity.
good yield (69%). Interestingly, even when the reac-
When 11 and 17 were employed in a Heck reaction
tion was performed at a lower temperature, for a using Conditions B, again the product of unusual re-
shorter time it was not possible to isolate 20 since gioselectivity 25 (58%) was obtained. When the one-
21a/b had already begun to form, prior to complete pot Heck–Stille conditions were employed (Condi-
consumption of the starting materials 11 and 17. tions C) the major product isolated from the reaction
When the mixture of double bond isomers 21a/b was mixture was 26, albeit only in a modest yield (32%,
allowed to stand in CDCl3 for 48 h at room tempera- from 11). Notwithstanding the modest yield of 26 iso-
ture quantitative conversion to 21b was observed. lated from this reaction sequence, it was the only dis-
Presumably, trace quantities of acid in the CDCl3 cat- cernable product formed in this reaction.
alyses this reaction.
A key difference in the reaction conditions that
We were also interested to see if we could access give rise to an initial Stille coupling (Conditions A,
tetracycle 21 from 2-chloroalkenyl triflate 10 as well. Scheme 3) as opposed to those that give an initial
We considered that the doubly vinylogous acid chlo- Heck reaction (Conditions B and C, Scheme 4) is
ride in the Stille product 22 may be suitably reactive most likely the use CuTC in the former, which acti-
to also proceed through to tetracyle 21, however, vates the stannane to transmetalation. Presumably, in
under standard Conditions A the reaction stopped at the absence of CuTC, where the Stille reaction is
22 (74%). Increasing the reaction temperature and slower, the Heck reaction becomes a more competi-
Scheme 3. Synthesis of Stille–Heck acceptors.
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Scheme 6. Heck–Stille reaction sequences. Conditions B:
Scheme 4. Stille–Heck reaction sequences of 11, 16 and 17.
Conditions A: PdACHTUNGTRENNUNG(dba)2 (0.06 equiv.), TFP (0.12 equiv.), LiCl
(5 equiv.), CuTC (0.10 equiv.), K2CO3 (4 equiv.), NMP.
Pd
C: Reaction under conditions B, then remove DCE and add
Pd(dba)2 (0.05 equiv.), TFP (0.10 equiv.), LiCl (3 equiv.),
CuTC (0.10 equiv.), NMP. Conditions D: Pd(dba)2
ACHTUNGTRENN(NUG PPh3)4, (0.10 equiv.), NaOAc (2 equiv.), DCE. Conditions
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
tive pathway and in the case of Conditions B the
dominating process.
(0.05 equiv.), TFP (0.10 equiv.), LiCl (3 equiv.), CuTC
(0.10 equiv.), NMP.
A surprising feature of the Heck reactions was the
observed regiochemistry, which is highly selective for
the reverse orientation to that usually seen for Heck orientation of the two substituents on palladium prior
reactions involving simple terminal olefins and mono- to carbopalladation.[9,10] Usually the s-bound substitu-
dendate ligands (PAr3).[8] Two tentative explanations ent (from the alkenyltriflate or halide) sterically
are provided here for this unexpected regiochemistry repels the substituent on the p-complexed olefin 27.
(Scheme 7). In the standard Heck reaction of a termi- This arrangement leads to delivery of the s-bound
nal olefin, the regiochemistry is determined by the substituent to the terminal end of the olefin 28, which
Scheme 5. Stille–Heck reaction sequence of 10 and 17.
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Alternation of Chemoselective Control in Stille–Heck and Heck–Stille Reaction
COMMUNICATIONS
The same explanation(s) would apply to the homol-
ogous Heck product 25.
The intramolecular Stille reaction of 23 also gave
an unusual outcome in the cine-substituted product 24
(Scheme 6). Whereas the intramolecular Stille reac-
tion of the homologous substrate 25 gave the usual,
ipso-substituted product 26. Based on previous mech-
anistic proposals for the cine- and ipso-Stille reactions,
it is likely that the common s,p-complexed intermedi-
ate 33 represent the branch point between these two
reaction pathways (Scheme 8).[11] Presumably, inter-
mediate 33 (n=1) prefers to undergo carbopallada-
tion to give 34, which then loses Me3SnBr to give car-
benoid 35. Subsequent 1,3-hydride shift (36) and re-
ductive elimination gives 24.[1] Complex 33 (n=2), on
the other hand, prefers to undergo transmetalation to
give palladacycle 37 and reductive elimination to give
25. This chemoselective difference in the fate of 33
(n=1) versus 33 (n=2) is difficult to explain but may
arise from a better accommodation of the 908 angle in
the square planar 8-membered palladacycle of 37
than in the seven-membered equivalent (not shown),
where the additional methylene allows a reduction of
strain in 37 and in the transition state leading to this
structure from 33 (n=2). The CuTC present in the re-
Scheme 7. Proposed mechanism for Heck regioselectivity.
gives a trans-vicinally substituted alkene 29 (unob-
served regioisomer of 23) upon b-hydride elmination.
One possible explanation of the reversal of the regio-
selectivity seen in 23 and 25 is that a favourable, non-
bonding interaction exists between the s-bound group
and the substituent on the p-complexed olefin, in the
case of 30 this interaction may be a p-stacking inter-
action between the dihydronaphthyl group and the
enone and/or a positive interaction between the bro-
mide and the stannane. Subsequent carbopalladation
gives complex 31, which gives 23 upon b-hydride
elimination. Alternatively, the reaction conditions and
or the nature of the substrates used may lend them-
selves to the attainment of a charged or polarised pal-
ladium complex 32, despite the fact that the usual re-
action conditions required for the formation of such
intermediates have not been employed.[8] Such com-
plexes tend to undergo carbopalladation in a manner
that directs the accumulating positive charge onto the
most substituted carbon of the olefin, directing the
palladium towards terminal end of the olefin, again
giving 31 then 23.
Scheme 8. Proposed mechanism for Stille regioselectivity.
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Kye-Simeon Masters and Bernard L. Flynn
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mina (neutral, Brockmann grade I) and washed through
with Et2O (20 mL). The organics were then extracted with
H2O (2ꢁ20 mL), the combined aqueous washings extracted
with Et2O (20 mL), the combined organics washed with
H2O (2ꢁ20 mL), dried over MgSO4 and the volatiles re-
moved under reduced pressure. Column chromatography of
the resulting brown crude on silica gel with EtOAc-PS (1:24
then 7:93) delivered bromide 18 as a pale yellow gum; yield:
129 mg (0.375 mmol, 75%). 1H NMR (300 MHz, CDCl3):
d=7.17 (mc, 3H), 6.89 (d, J=7.5 Hz, 1H), 5.71 (mc, 1H),
4.86–4.81 (m, 2H), 3.02–2.97 (m, 2H), 2.92–2.78 (m, 2H),
2.70–2.61 (m, 1H), 2.56 (t, J=6.6 Hz, 2H), 2.45–2.35 (m,
1H), 2.19–2.08 (tt, J=6.6, 6.9 Hz, 2H); 13C NMR
(75.5 MHz, CDCl3): d=195.2 (C=O), 155.5 (C), 137.4 (C),
136.1 (C), 135.2 (CH), 134.0 (C), 132.4 (C), 127.9 (2ꢁ sig-
nals, CH), 127.0 (CH), 124.4 (CH), 121.4 (C), 115.7 (CH2),
38.3 (CH2), 34.3 (CH2), 31.9 (CH2), 30.5 (CH2), 29.3 (CH2),
22.7 (CH2); HR-MS (+ESI): m/z=365.0509 (79Br), 367.0498
(81Br); calcd. for [C19H19BrNaO]+ (M+Na+) (79Br): 365.0512,
(81Br): 367.0491.
action mixture is likely to facilitate one or both of
these processes, most likely through interaction with
33 (n=2) and 34 to faciltate loss of Me3SnBr.
The reaction processes described here offer new
possibilities for accessing polycyclic ring systems in a
manner that can afford significant scaffold diversity
from a discrete set of substrates. In our ongoing stud-
ies in this area we will seek to better define the sub-
strate and reaction condition requirements for the un-
usual regioselectivity observed in the Heck and Stille
reaction processes performed in this work.
Experimental Section
General Remarks
Tetrahydrofuran (THF) was distilled from sodium wire and
benzophenone (sodium benzophenone ketyl) and dichloro-
ethane (DCE) from CaH2 under N2(g). Petroleum spirit (PS,
40–608C fraction) was distilled prior to use. N-Methylpyrro-
lidinone (NMP), dichloromethane (DCM), ethyl acetate
(EtOAc), and diethyl ether (Et2O) were used as commer-
cially supplied (anhydrous/reagent grade). Thin layer chro-
matography (TLC) was performed with 0.25 mm silica gel
60F plates with 254 nm fluorescent indicator (Merck) and
plates were visualised with UV light and vanillin or anisal-
dehyde dip and heating. Products were isolated using silica
gel 60, 230–400 mesh (Merck) or alumina (neutral, Brock-
mann grades I or II). Nuclear magnetic resonance (NMR)
6-Methyl-2,3,7,8-tetrahydrobenzo[c]phenanthren-
4(1H)-one (19)
This reaction was performed as described above for the cou-
pling of 11 and 16 to give 18 (Conditions A) except the reac-
tion mixture was heated to 858C for 3 h. The reaction vessel
was cooled and the contents poured onto a plug of alumina
(neutral, Brockmann grade I), and washed through with
Et2O (20 mL). The organics were then washed with H2O
(2ꢁ20 mL), the aqueous layer extracted with Et2O (20 mL),
the combined organics washed with H2O (2ꢁ10 mL), dried
over MgSO4 and the volatiles removed under reduced pres-
sure. Column chromatography of the crude on silica gel with
EtOAc-PS (3:47 then 7:93) delivered tetracycle 19 as a pale
yellow solid; yield: 43 mg (0.164 mmol, 54%); mp 128–
1298C. 1H NMR (300 MHz, CDCl3): d=7.97 (s, 1H), 7.63
(d, J=6.6 Hz, 1H), 7.31–7.38 (m, 3H), 3.30 (t, J=5.7 Hz,
2H), 2.81 (s, 4H), 2.75 (t, J=6.0 Hz, 2H), 2.44 (s, 3H), 2.07
(tt, J=6.0, 5.7 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d=
198.9 (C=O), 144.4 (C), 139.7 (C), 138.8 (C), 134.7 (C),
134.0 (C), 133.3 (C), 131.7 (C), 128.7 (CH), 128.0 (CH),
127.4 (CH), 127.2 (CH), 125.8 (CH), 39.1 (CH2), 30.6 (CH2),
29.1 (CH2), 26.8 (CH2), 24.1 (CH2), 19.8 (CH3); HR-MS
(EI): m/z=262.1352, calcd. for [C19H18O]+ (M+): 262.1352.
1
spectra were recorded at 300.1 MHz for H and 75.5 MHz
for 13C and referenced to residual protonated solvent.
13C NMR spectra assignments were made on the basis of a
J-modulated spin echo (J-MOD) experiment. Infrared spec-
tra (IR) were obtained on an FT-IR spectrometer. Low res-
olution mass spectrometry (LR-MS) and high resolution
mass spectrometry (HR-MS) were performed using an EI,
ESI or APCI ion source. Melting points were determined
with an electrothermal melting point apparatus and are un-
corrected.
Degas procedure: A typical degassing procedure is as fol-
lows: The solvent was stirred vigorously and a high vacuum
[<5 mbar] was applied for 0.1 h. The flask was then backfil-
led with N2(g), and the procedure repeated (ꢁ3) in order to
remove all dissolved gases. For volatile solvents (e.g., DCE)
the procedure was performed at À408C.
7-Methyl-5,6,9,11,12,13-hexahydrobenzo
hepta[1,2-a]naphthalen-10-one (21b)
ACHTUNGTRENUN[NG 6,7]cyclo-
AHCTUNGTRENNUNG
2-Allyl-3-(2-bromo-3,4-dihydronaphthalen-1-yl)cyclo-
hex-2-enone (18)
Substrates 11 and 17 were coupled as described for 19 (Con-
ditions A, 17 replaces 16) except that the reaction was
heated to 858C for 4 h. After this time the reaction mixture
was cooled and diluted with EtOAc (20 mL), washed with
brine (10 mL), H2O (3ꢁ10 mL), dried over MgSO4 and the
volatiles removed under reduced pressure. Column chroma-
tography of the crude product on silica gel with EtOAc-PS
(1:24) delivered tetracycles 21a/b as a yellow gum; yield:
69%. This product was isolated as a mixture of the terminal
olefin (direct Heck product) 21a and the double-bond in-
ternalised species 21b (1:1), which converted entirely to the
thermodynamically more stable olefin 21b upon standing in
Conditions A: Lithium chloride (106 mg, 2.50 mmol) and
sodium carbonate (Na2CO3, 160 mg, 1.50 mmol) were flame
dried carefully in a round-bottomed flask under vacuum and
cooled under N2(g). NMP (4 mL) and 2-bromoalkenyl triflate
11 (179 mg, 0.50 mmol) were added the suspension degassed
(General Remarks). PdACTHNUTRGNE(NUG dba)2 (28.4 mg, 0.05 mmol), TFP
(23.2 mg, 0.10 mmol), stannane 16 (200 mg, 0.67 mmol) and
CuTC (9.5 mg, 0.05 mmol) were added and the degas proce-
dure repeated. The reaction mixture was heated to 558C for
4 h, after this time 11 was completely consumed (TLC). The
reaction mixture was cooled and poured onto a plug of alu-
1
CDCl3 for 48 h. H NMR (300 MHz, CDCl3): d=7.23–7.14
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Alternation of Chemoselective Control in Stille–Heck and Heck–Stille Reaction
COMMUNICATIONS
(m, 3H), 7.00 (d, J=7.2 Hz, 1H), 5.73 (dt, J=7.8, 1.2 Hz,
1H), 3.52 (ddd, J=12.6, 7.5, 1.2 Hz, 1H), 2.88 (m, 1H), 2.82
(m, 1H), 2.82–2.71 (m, 2H), 2.62–2.53 (m, 1H), 2.41–2.30
(m, 1H), 2.28–2.21 (m, 1H), 2.14–2.08 (m, 1H), 2.05–2.02
(m, 1H), 1.93 (d, J=1.2 Hz, 3H), 1.97–1.88 (m, 1H), 1.66
(dd, J=12.6, 6.6 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=
197.7 (C=O), 149.1 (C), 142.3 (C), 137.7 (C), 136.5 (C),
134.7 (C), 134.1 (C), 133.7 (C), 128.4 (CH), 127.9 (CH),
127.1 (CH), 126.8 (CH), 126.3 (CH), 38.2 (CH2), 29.8 (CH2),
28.2 (CH2), 26.2 (CH2), 23.87 (CH2), 23.6 (CH2), 22.0 (CH3);
LR-MS (+ESI); m/z=277.3 (100%, M+H+), 259.3 (13%,
M+H+ÀH2O); HR-MS (ESI): m/z=299.1407, calcd.
[C20H20NaO]+ (M+Na+): 299.1412.
with H2O (3ꢁ10 mL), the combined aqueous washings ex-
tracted with Et2O (10 mL), the combined organics washed
with brine (10 mL), dried with MgSO4 and the volatiles re-
moved under reduced pressure. Chromatography of the
crude on silica gel chromatography with DCM-EtOAc-PS
(50:3:47) delivered tetracycle 24 as a brown gum; yield:
10.1 mg (0.038 mmol, 81%).
Conditions C: As per the procedure for 23 above however
prior to work-up the solvent (DCE) was carefully removed
under vacuum and replaced with NMP (1.5 mL) which was
degassed (see General Remarks). PdACTHNUTRGENUG(N dba)2 (2.7 mg,
0.005 mmol), TFP (18.5 mg, 0.08 mmol) and CuTC (3.8 mg,
0.02 mmol) were added and the degas procedure repeated.
The reaction mixture was stirred at 658C for 20 h. After this
time the reaction mixture was cooled and passed through a
plug of alumina (neutral, Brockmann grade I), the organics
were flushed through with Et2O (30 mL) and washed with
H2O (3ꢁ30 mL). The combined aqueous washings were ex-
tracted with Et2O (10 mL), the combined organics washed
with H2O (10 mL), dried over MgSO4 and the solvent re-
moved under reduced pressure. Planar chromatography of
the crude on silica gel with DCM-EtOAc-PS (50:3:47) deliv-
2-[2-(2-Bromo-3,4-dihydronapthylen-1-yl)allyl]-3-
(trimethylstannyl)cyclohex-2-enone (23)
Conditions B:
A Schlenk tube with NaOAc (33 mg,
0.40 mmol) was flame dried under vacuum, cooled under
N2(g) and 2-bromoalkenyl triflate 11 (72.0 mg, 0.20 mmol)
then stannane 16 (32 mg, 0.12 mmol) were added. Dichloro-
ethane (DCE, 2 mL) was added by syringe, the reaction
mixture cooled to À408C and degassed (see General Re-
ered tetracycle 24 as
a brown gum; yield: 26.8 mg
(0.102 mmol, 51% from 2-bromoalkenyl triflate 11).
1H NMR (300 MHz, CDCl3): d=7.62 (d, J=7.2 Hz, 1H),
7.14 (mc, 3H), 5.94–5.88 (mc, 1H), 5.61 (d, J=8.1 Hz, 1H),
5.36 (s, 1H), 4.95 (s, 1H), 3.13 (d, J=15.9 Hz, 1H), 2.90–
2.74 (m, 2H), 2.72–2.64 (m, 2H), 2.58–2.45 (m, 3H), 2.22 (t,
J=7.5 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d=211.0 (C=
O), 150.4 (C), 147.8 (C), 137.2 (C), 136.7 (C), 132.7 (CH),
131.6 (C), 127.8 (CH), 127.1 (CH), 127.1 (CH), 126.3 (CH),
124.2 (CH), 103.2 (CH2), 60.7 (C), 45.1 (CH2), 38.4 (CH2),
29.2 (CH2), 26.1 (CH2), 22.8 (CH2); LR-MS (+ESI): m/z=
263.4, (M+H+); HR-MS (+ESI): m/z=263.1426, calcd. for
[C19H19O]+ (M+H+): 263.1436.
marks), then PdACHTUNGTRENNUNG(PPh3)4 (32 mg, 0.02 mmol) added and the
degas procedure repeated. The reaction mixture was heated
at 808C for 1 h, after which time another portion of stan-
nane 16 (32 mg, 0.12 mmol) was added, heating continued
for 1 h, then another portion of stannane 16 (32 mg,
0.12 mmol) added and heating continued for 1 h. After this
time the solution was cooled to room temperature, diluted
with Et2O (30 mL) and washed with H2O (3ꢁ10 mL). The
organics were combined, dried with MgSO4 and the volatiles
removed under reduced pressure. Chromatography of the
crude on silica gel with EtOAc-PS (3.5:96.5) delivered 23 as
a yellow solid; yield: 73 mg (0.144 mmol, 72%); mp 110–
1
1128C. H NMR (300 MHz, CDCl3): d=7.51 (d, J=7.8 Hz,
1H), 7.23 (t, J=7.8 Hz, 1H), 7.16 (t, J=7.2 Hz, 1H), 7.10
(d, J=7.2 Hz), 5.20 (s, 1H), 4.98 (s, 1H), 3.3–3.1 (sbr, 2H),
2.90–2.82 (sbr, 4H), 2.53 (t, J=5.4 Hz, 2H), 2.38 (t, J=
6.6 Hz, 2H), 1.90 (mc, 2H), 0.29 (s, SnMe3, 9H); 13C NMR
(75.5 MHz, CDCl3): d=194.4 (C=O), 169.3 (C), 145.5 (C),
144.9 (C), 139.5 (C), 134.2 [2ꢁ non-equivalent (C) signals],
127.2 (CH), 127.2 (CH), 126.8 (CH), 126.2 (CH), 121.3 (C),
116.6 (CH2), 38.7 (CH2), 38.4 (CH2), 35.1 (CH2), 34.1 (CH2),
29.6 (CH2), 24.1 (CH2); SnMe3 not visible in the spectrum
(need lower than 0 ppm); HR-MS (+APCI): m/z=
507.0341, calcd. for [C22H28BrOSn]+ (M+H+): 507.0340.
2-[3-(2-Bromo-3,4-dihydronapthylen-1-yl)but-3-enyl]-
3-(trimethylstannyl)cyclohex-2-enone (25)
Subtrates 11 and 17 were coupled as described for com-
pound 23 above (Conditions B) except that the reaction was
heated to 808C for 3.5 h. Planar chromatography of the
crude reaction mixture on silica gel with EtOAc-PS (1:9) de-
livered stannane 25 as a yellow oil; yield: 58%. 1H NMR
(300 MHz, CDCl3): d=7.28 (mc, 1H), 7.20 (mc, 2H), 7.15
(mc, 1H), 5.47 (d, J=1.2 Hz, 1H), 5.07 (d, J=1.2 Hz, 1H),
2.90 (sbr, 4H), 2.51 (t, J=5.7 Hz, 2H), 2.51 (br m, 2H), 2.41
(t, J=6.6 Hz, 2H), 2.27 (br m, 2H), 2.17–2.02 (dt, J=6.6,
5.7 Hz, 2H), 0.26 (s, SnMe3, 9H); 13C NMR (75.5 MHz,
CDCl3): d=196.5 (C=O), 166.6 (C), 147.6 (C), 146.7 (C),
139.2 (C), 138.3 (C), 134.03 (C), 127.4 (CH), 127.2 (CH),
126.7 (CH), 125.2 (CH), 121.5 (C), 116.1 (CH2), 38.8 (CH2),
36.3 (CH2), 34.9 (CH2), 33.6 (CH2), 32.4 (CH2), 29.5 (CH2),
1’-Methylene-1’,3’,4’,5’-tetrahydrospiro[cyclohex-2-
ene-1’,2’-cyclopenta[a]naphthalene]-6-one (24)
Conditions D: LiCl (6 mg, 0.14 mmol) was flame-dried in a
Schlenk flask under vacuum and back-filled with N2(g), then
NMP (1 mL) was added and the solution degassed (see
General Remarks). To this solution bromostannane 23
24.1 (CH2), À8.4 Sn
ACHTUNGTERN(NUNG CH3); HR-MS (EI): m/z=543.0297, cal-
culated [C23H29BrNaOSn]+ (M+Na+): 543.0316.
(24.0 mg, 0.047 mmol), PdACTHNUTRGNE(UNG dba)2 (2.7 mg, 0.005 mmol), TFP
(2.3 mg, 0.01 mmol) and CuTC (1.0 mg, 0.005 mmol) were
added and the degas procedure repeated. The reaction mix-
ture was stirred at 658C for 3 h, during which time 23 was
completely consumed by TLC. The reaction mixture was
cooled then poured on a plug of alumina (Brockmann grade
II), washed through with Et2O (10 mL), the organics washed
11-Methylene-2,34,5,6,11,12,13-octahydrobenzoACHTUNGTRENNUNG[3,4]-
cycloheptaACTHNUTRGNEUNG[1,2-a]naphthalene-1-one (26)
Subtrates 11 and 17 were coupled as described for com-
pound 24 above (Conditions C, 17 replaces 16) except that
the reaction was heated at 658C for 14 h. Planar chromatog-
Adv. Synth. Catal. 2009, 351, 530 – 536
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
535

Kye-Simeon Masters and Bernard L. Flynn
COMMUNICATIONS
raphy of the crude on silica gel with DCM-EtOAc-PS
(50:3:47) delivered tetracycle 26 as a pale yellow oil which
became a white solid upon standing; yield: 32% (from 2-
[2] We have recently reported a related Stille–Heck pro-
cess for gaining access to the tetracylic core of Frondo-
sin D: K.-S. Masters, B. L. Flynn, J. Org. Chem. 2008,
73, 8081–8084.
1
bromoalkenyl triflate 11):mp 84–868C. H NMR (300 MHz,
CDCl3): d=7.45 (mc, 1H), 7.18 (mc, 3H), 5.14 (d, J=1.5 Hz,
1H), 4.73 (d, J=1.5 Hz, 1H), 2.87 (t, J=7.5 Hz, 2H), 2.87
(t, J=6.9 Hz, 2H), 2.45 (mc, 8H), 2.02 (mc, 2H); 13C NMR
(75.5 MHz, CDCl3): d=198.1 (C=O), 158.9 (C), 145.0 (C),
138.2 (C), 136.0 (C), 135.1 (C), 133.8 (C), 128.9 (C), 127.6
(CH), 127.5 (CH), 126.6 (CH), 126.1 (CH), 114.1 (CH2),
45.5 (CH2), 38.0 (CH2), 28.5 (CH2), 28.15 (CH2), 24.9 (CH2),
23.0 (CH2), 22.1 (CH2); LR-MS (+APCI): m/z=277.0; HR-
MS (+ESI): m/z=299.1414, calcd. for [C20H20NaO]+
(M+H+): 299.1406.
[3] B. Sreedhar, P. S. Reddy, M. Madhavi, Synth. Commun.
2007, 37, 4149–4156.
[4] D. H. Fitzgerald, K. M. Muirhead, N. P. Botting,
Bioorg. Med. Chem. 2001, 9, 983–989.
[5] A yield of 58% was achieved with triflic anhydride
only, a yield of 72% was obtained with N-pyrid-2-yl tri-
flimide only.
[6] a) E. Piers, J. R. Grierson, J. Org. Chem. 1977, 42,
3755–3757; b) D. J. Kerr, A. C. Willis, B. L. Flynn, Org.
Lett. 2004, 6, 457–460.
[7] E. Piers, H. E. Morton, J. M. Chong, Can. J. Chem.
1987, 65, 78–87.
Supporting Information
[8] For reviews on the regiochemical alternation of Heck
reactions involving monodendate and bidendate li-
gands, see: a) W. Cabri, I. Candiani, Acc. Chem. Res.
1995, 28, 2–7; b) M. Larhed, A. Hallberg, in: Hand-
book of Organopalladium Chemistry for Organic Syn-
thesis, 1st edn., Vol. I, (Eds.: E Negishi, A. de Meijere),
John Wiley and Sons, Inc., Chicester, 2002, pp 1133–
1178.
[9] Although there have been some previous reports on
cine-Stille reactions (see ref.[10] and references cited
therein), to the best of the authors knowledge this is
the first intramolecular example.
[10] E. Fillion, N. J. Taylor, J. Am. Chem. Soc. 2003, 125,
12700–12701.
[11] Both ipso- and cine-substitution mechanism are likely
to involve prior p-complexation of the vinylstannane,
see ref.[10] and V. Farina, B. J. Krishman, J. Am. Chem.
Soc. 1991, 113, 9585–9595.
Detailed experimental procedures for all other compounds
and spectral data are provided as Supporting Information.
References
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536
asc.wiley-vch.de
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 530 – 536