Preparation of functionalized cyclic enol phosphates by halogen-magnesium exchange and directed deprotonation reactions

Article abstract of DOI:10.1021/jo100763f

(Figure presented) Cyclic enol phosphates were magnesiated by a halogen/magnesium exchange reaction or deprotonation using TMP-derived magnesium amide bases. The resulting magnesium reagents react readily with a wide range of electrophiles like allyl bromides and acid chlorides or can be used in Pd-catalyzed cross-coupling reactions. Several optically pure enol phosphates were prepared starting from readily available d-(+)-camphor derivatives.

Full text of DOI:10.1021/jo100763f

pubs.acs.org/joc
Preparation of Functionalized Cyclic Enol Phosphates by
Halogen-Magnesium Exchange and Directed Deprotonation Reactions
Fabian M. Piller, Tomke Bresser, Markus K. R. Fischer, and Paul Knochel*
€
€
Ludwig-Maximilians-Universitat Munchen Department Chemie Butenandtstrasse 5-13,
Haus F, 81377 Mu€nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received April 26, 2010
Cyclic enol phosphates were magnesiated by a halogen/magnesium exchange reaction or deprotona-
tion using TMP-derived magnesium amide bases. The resulting magnesium reagents react readily
with a wide range of electrophiles like allyl bromides and acid chlorides or can be used in Pd-catalyzed
cross-coupling reactions. Several optically pure enol phosphates were prepared starting from readily
available D-(þ)-camphor derivatives.
SCHEME 1. Rearrangement of Lithiated Enol Phosphates to
the Corresponding β-Keto Phosphonate
1. Introduction
Enol phosphates have found applications as insecticides1
and phosphatase inactivators.2 Additionally, they can be
used as versatile intermediates for the regioselective prepara-
tion of substituted double bonds. Several methods have been
developed allowing efficient transition-metal-catalyzed cross-
coupling reactions with these electrophiles.3 In fact, enol
phosphates are a useful synthetic alternative to the correspond-
ing triflates since they are generally less expensive and more
stable. Their preparation is conveniently performed starting
either from enolizable ketones or R-halo carbonyl com-
pounds.1 The synthesis of lithiated enol phosphates of type 1
via halogen-lithium exchange or deprotonation using LDA
has already been described by Wiemer.4 However, these
lithium reagents do not react with electrophiles (Eþ) but
rearrange to the corresponding β-keto phosphonates 2 in good
yields (Scheme 1).
As organomagnesium reagents are less reactive than organo-
lithium reagents, it is expected that the corresponding magne-
sium reagents are more stable. In recent years, we have found that
LiCl greatly facilitates the preparation of organomagnesium,5
organozinc,6 organoindium,7 and other organometallic8 re-
agents. Thus, i-PrMgCl LiCl (3)5a allows the preparation of
(1) (a) Lichtenthaler, F. W. Chem. Rev. 1961, 61, 607. (b) Ding, Y.;
Huang, X. Heteroatom Chem. 2003, 14, 304.
(2) (a) Stowell, J. K.; Widlanski, T. S. J. Am. Chem. Soc. 1994, 116, 789.
3
various alkenylmagnesium reagents starting from the corre-
sponding alkenyl iodides.9 Herein, we wish to report that
(b) Widlanski, T. S. US Patent 5,714,361.
(3) (a) Takai, K.; Sato, M.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
1984, 57, 108. (b) Cahiez, G.; Gager, O.; Habiak, V. Synthesis 2008, 16, 2636.
(c) Miller, J. A. Tetrahedron Lett. 2002, 43, 7111. (d) Larsen, U. S.; Martiny,
L.; Begtrup, M. Tetrahedron Lett. 2005, 46, 4261.
(6) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040. (b) Wunderlich, S. H.; Knochel, P.
Angew. Chem., Int. Ed. 2007, 46, 7685.
(7) (a) Chen, Y.-H.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 7648.
(b) Chen, Y.-H.; Sun, M.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 2236.
(8) Aluminum: (a) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed.
(4) (a) Calogeropoulou, T.; Hammond, G. B.; Wiemer, D. F. J. Org. Chem.
1987, 52, 4185. (b) Baker, T. J.; Wiemer, D. F. J. Org. Chem. 1998, 63, 2613.
(5) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
(b) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed. 2005,
45, 159. (c) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.;
Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 6802. (d) Piller, F. M.; Metzger,
A.; Schade, M. A.; Haag, B. A.; Gavryushin, A.; Knochel, P. Chem.;Eur. J.
2009, 15, 7192. (e) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 2958. (f) Clososki, G. C.; Rohbogner, C. J.;
Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7681. (g) Rohbogner, C. J.;
Clososki, G. C.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 1503. (h)
Rohbogner, C. J.; Wirth, S.; Knochel, P. Org. Lett. 2010, 12, 1984.
€
2009, 48, 1501. (b) Blumke, T. D.; Chen, Y.-H.; Knochel, P. Nature Chem.
2010, 2, 313. Manganese: (c) Wunderlich, S. H.; Kienle, M.; Knochel, P.
Angew. Chem., Int. Ed. 2009, 48, 7256. Iron: (d) Wunderlich, S. H.; Knochel,
P. Angew. Chem., Int. Ed. 2009, 48, 9717. (e) Wunderlich, S. H.; Knochel, P.
Chem.;Eur. J. 2010, 16, 3304.
(9) (a) Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215. (b)
Ren, H.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2005, 543.
DOI: 10.1021/jo100763f
r
Published on Web 06/09/2010
J. Org. Chem. 2010, 75, 4365–4375 4365
2010 American Chemical Society

Piller et al.
JOCFeatured Article
SCHEME 2. Strategy for the Functionalization of Enol Phos-
phates by Halogen/Magnesium Exchange or Deprotonation
Reactions
TABLE 1. Products Obtained by the Reaction of 10a with Various
Electrophiles
SCHEME 3. Preparation and Reactions of the Magnesium
Reagent 10a with Electrophiles
i-PrMgCl LiCl (3) allows us to prepare magnesiated enol
3
phosphates of type 4 starting from the corresponding bromides
or iodides of type 5. The presence of LiCl is essential since the
use of i-PrMgCl does not lead to a convenient exchange
reaction giving the Mg-species 4 at all. Furthermore, magne-
sium amide bases such as TMPMgCl LiCl5e and TMP2-
3
Mg 2LiCl5f-h (TMP = 2,2,6,6-tetramethylpiperidyl) are able
3
to directly metalate cycloalkenyl phosphates of type 6 provid-
ing an alternative preparation of enol phosphates of type 4.
After the addition of an electrophile (Eþ), functionalized enol
phosphates of type 7 can be obtained (Scheme 2).
aYield of analytically pure product. bThe use of TMSCl did not lead
to the silylated compound. cObtained after transmetalation with
CuCN 2LiCl (20-100 mol %). dObtained after transmetalation with
3
ZnCl2 (1.1 equiv) and Pd(dba)2 (5 mol %) and tfp (10 mol %) catalyzed
cross-coupling.
2. Results and Discussion
(entry 3). The transmetalation of the magnesium reagent 10a
Thus, starting from 2-iodocyclopent-2-enone (8), the 5-
membered cyclic enol phosphate 9 was prepared by reduction
with L-Selectride and quenching of the resulting enolate with
diethyl chlorophosphate.4b The I/Mg-exchange reaction of 9
with CuCN 2LiCl11 (1.1 equiv, -20 °C, 30 min) provides an
3
intermediate copper reagent which undergoes various Cu(I)-
mediated reactions. Thus, when reacting this copper reagent
with allyl bromide (25 °C, 1 h), the allylated enol phosphate 11d
is obtained in 82% yield (entry 4). Similarly, the reaction of this
copper intermediate with benzoyl chloride (0 °C, 2 h) provides
the expected ketone 11e in 84% yield (entry 5). A 1,4-addition
to 3-iodocyclohexenone also proceeds smoothly at 0 °C within
2 h, and the functionalized enol phosphate 11f is obtained in
71% yield (entry 6). Additionally, a transmetalation with
ZnCl2 leads to a zinc reagent which undergoes a Pd-catalyzed
Negishi cross-coupling reaction12 by using Pd(dba)2 (5 mol %)
and tri(2-furyl)phosphine (tfp, 10 mol %)13 as a catalytic
with i-PrMgCl LiCl (3) proceeds smoothly and yields the
3
alkenylmagnesium reagent 10a within 5 min at -50 °C. Under
these mild reaction conditions, no rearrangement to the β-keto
phosphonate is observed. The magnesium reagent 10a can then
be reacted with various electrophiles and provides the corres-
ponding 2-substituted cyclic enol phosphates 11a-g in 71-88%
yield (Scheme 3 and Table 1).
Thus, the magnesium reagent 10a was reacted with
PhSO2SPh to give the thioether 11a in 83% yield (Table 1,
entry 1). The treatment of the Grignard reagent 10a with
1-(N,N-diethylamino)methylbenzotriazole10 (-50 to 25 °C,
1 h) leads to the diethyl aminomethyl derivative 11b in 82%
yield (entry 2), while the reaction with TMS-CN (-50 to
þ25 °C, 3 h) affords the silylated product 11c in 88% yield
(11) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(12) (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (b) Negishi, E.;
Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980, 102, 3298. (c) Zeng,
X.; Quian, M.; Hu, Q.; Negishi, E. Angew. Chem., Int. Ed. 2004, 43, 2259.
(13) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 112, 9585. (b)
Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org.
(10) Katritzky, A. R.; Yannokopoulou, K.; Kuzmierkiewicz, W.;
Aurrecoechea, J. M.; Palenik, G. J.; Koziol, A. E.; Szczesniak, M. J.
Chem. Soc., Perkin Trans. 1 1987, 12, 2673.
€
Chem. 1994, 59, 5905. (c) Klement, I.; Rottlander, M.; Tucker, C. E.; Majid,
T. N.; Knochel, P.; Venegas, P.; Cahiez, G. Tetrahedron 1996, 52, 7201.
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SCHEME 4. Preparation and Reactions of the Magnesium
Reagent 10b with Electrophiles
SCHEME 5. Preparation and Reactions of the Magnesium
Reagent 16 with Electrophiles
TABLE 3. Products Obtained by the Reaction of 16 with Various
Electrophiles
TABLE 2. Products Obtained by the Reaction of 10b with Various
Electrophiles
aYield of analytically pure product. bObtained after transmetalation
c
with CuCN 2LiCl (20-100 mol %). Obtained after transmetalation
3
aYield of analytically pure product. bObtained after transmetalation
with ZnCl2 (1.1 equiv) and Pd(dba)2 (4 mol %) and tfp (12 mol %)
catalyzed cross-coupling.
c
with CuCN 2LiCl (20-100 mol %). Obtained after transmetalation
3
with ZnCl2 (1.1 equiv) and Pd(dba)2 (4 mol %) and tfp (12 mol %)
catalyzed cross-coupling.
corresponding magnesium reagent 16 is then obtained by
deprotonation of 15 with TMP2MgCl 2LiCl (1.1 equiv,
3
system. Thus, the reaction of the zinc reagent derived from 10a
with tert-butyl 4-iodobenzoate leads to the desired cross-
coupling product 11g in 79% yield (Table 1, entry 7).
25 °C, 30 min). At this temperature, no rearrangement to the
β-keto phosphonate is observed (see Scheme 1). After reaction
of the Grignard reagent 16 with electrophiles such as allyl
bromide, benzoyl chloride, S-methyl methanethiosulfonate, or
ethyl 4-iodobenzoate in a Negishi cross-coupling12 reaction
(after transmetalation to zinc), the expected norbornene
derivatives 17a-d are given in 73-96% yield (Scheme 5 and
Table 3).
Similar results were obtained by generating the magnesium
reagent 10b using the magnesium amide TMP2MgCl 2LiCl.5f-h
3
Deprotonation of cyclopentanone (12) with LiTMP (1.1 equiv,
-78 °C, 1 h) and quenching the resulting enolate with diethyl
chlorophosphate gives the enol phosphate 13 in 86% yield. The
treatment of 13 with TMP2Mg 2LiCl (1.1 equiv) at -10 °C
Camphor derivatives are often used as chiral auxiliaries in
stereoselective reactions.14 Developing a functionalization of
the camphor skeleton would therefore be a highly desirable
process. Starting from D-(þ)-camphor (18) or from commer-
cially available D-(þ)-bromocamphor (19), the enol phosphates
20 and 21 were prepared by deprotonation with LDA (1.1
equiv, -78 °C, 1.5 h) and quenching of the formed enolate with
diethyl chlorophosphate in 68-82% yield. The corresponding
magnesium reagent 22 was smoothly generated either by
3
cleanly provides the corresponding magnesium reagent 10b
within 2 h due to the high coordinating effect of the phosphate
group. The magnesium reagent 10b readily undergoes Cu(I)-
catalyzed allylation reactions11 or palladium-catalyzed cross-
coupling reactions12 (after transmetalation to zinc) to give the
products 11d,h-j in 45-58% yield (Scheme 4 and Table 2).
This reaction sequence can also be extended to bicyclic
systems. Starting from bicyclo[2.2.1]heptan-2-one (14), the
bicyclic alkenyl phosphate 15 was prepared by deproto-
nation with LDA (1.1 equiv, -78 °C, 1.5 h) and quenching
of the resulting enolate with diethyl chlorophosphate.4a The
(14) (a) Oppolzer, W. Tetrahedron 1987, 43, 1969. (b) Chelucci, G. Chem.
Soc. Rev. 2006, 35, 1230.
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SCHEME 6. Preparation and Magnesiation of Enol Phosphates 20 and 21 via a Deprotonation Reaction (Method A) or a Br/Mg
Exchange Reaction (Method B)
treatment of 20 with TMP2MgCl 2LiCl5f-h (1.1 equiv, 25 °C,
E/Z selectivity. Aliphatic aldehydes react as well, and after the
treatment of cyclohexane carboxyaldehyde with the magne-
sium reagent 22, the elimination product 25c is obtained in
70% yield and 96:4 E/Z selectivity (Scheme 7).
3
30 min) or by the reaction of 21 with i-PrMgCl LiCl5a (3: 1.1
3
equiv, 25 °C, 2 h, Scheme 6).
Interestingly, the bromo-enol phosphate 21 undergoes a
fast Br/Mg-exchange reaction, therefore avoiding the use of
the corresponding iodide. The magnesium reagent 22 has a
similar reactivity, regardless of its preparation method.
Thus, the Grignard reagent 22 generated by deprotonation
3. Conclusion
In summary, we have reported different procedures allowing
an R-magnesiation of cyclic enol phosphates by a halogen/
with TMP2MgCl 2LiCl or Br/Mg exchange reacts with
3
magnesium exchange reaction using i-PrMgCl LiCl or a de-
protonation reaction using TMP2MgCl 2LiCl. The resulting
allylic bromides using a copper(I) catalysis,11 giving the
allylated products 23a,b in 62-85% yield (Table 4, entries
1-3). Similarly, the cycloalkenylmagnesium reagent 22 un-
dergoes acylation reactions with various acid chlorides using
3
3
magnesium reagents react readily with various electrophiles
like sulfur electrophiles, allyl bromides, and acid chlorides or
can be used in Pd-catalyzed cross-coupling reactions. Several
optically pure enol phosphates were prepared starting from
readily available D-(þ)-camphor derivatives. Furthermore, the
reaction of a camphor derived magnesium reagent with alde-
hydes furnishes, after an elimination, the corresponding R,β-
unsaturated enones. Extensions of this work are currently
underway in our laboratories.
CuCN 2LiCl (20 to 100 mol %),11 and the expected ketones
3
23c-d are provided in 67-82% yield (entries 4-6). Addi-
tionally, the use of ethyl cyanoformate allows the synthesis of
the ester 23e in 72% yield (entry 7). Thioethers are easily
prepared by quenching the Grignard reagent 22 with thio-
sulfonates. Using PhSO2SMe or PhSO2SPh as electrophiles,
the corresponding methyl and phenyl thioethers 23f and 23g
were obtained in 65 and 73% yield (entries 8 and 9). After a
transmetalation with ZnCl2 (1.1 equiv), the resulting organo-
zinc reagents undergo Negishi cross-coupling reactions.12
Using Pd(dba)2 (2 mol %) and tfp (4 mol %)13 or [Pd(PPh3)4]
(4 mol %) as catalytic system, ethyl 4-iodobenzoate and
4-iodobenzonitrile are coupled to the camphor core in
58-74% yield (entries 10 and 11). Even the electron-rich
3-bromoanisole can be used in a cross-coupling reaction by
using Buchwald’s S-Phos ligand15 (4 mol %) and Pd(OAc)2
(2 mol %) yielding the arylated camphor derivative 23j in
69% yield (entry 12).
4. Experimental Section
General Considerations. All reactions were carried out under
an argon atmosphere in flame-dried glassware. Syringes which
were used to transfer anhydrous solvents or reagents were
purged with argon prior to use. THF was continuously refluxed
and freshly distilled from sodium benzophenone ketyl under
nitrogen. Yields refer to isolated yields of compounds estimated
to be >95% pure as determined by 1H NMR (25 °C) and
capillary GC. Column chromatographical purifications were
performed using SiO2 (0.040-0.063 mm, 230-400 mesh
ASTM). All reagents were obtained from commercial sources.
TmpH, liquid aldehydes, and acid chlorides were distilled prior
to use. The completion of the metalation was checked by GC
analysis of reaction aliquots quenched with a solution of 3 drops
An unexpected reaction pathway was observed when react-
ing Grignard reagent 22 with aldehydes. The intermediate
magnesium alcoholates of type 24 undergo a spontaneous
elimination to give the R,β-unsaturated ketones 25a-c16 with
an excellent E/Z selecitivity as shown by NMR analysis (see
the Supporting Information). Thus, after the reaction of the
Grignard reagent 22 with 4-cyanobenzaldehyde, the ketone
25a is obtained in 72% yield and >98:2 E/Z-selectivity.
Similarly, 4-bromobenzaldehyde gives a similar elimination
and yields the unsaturated ketone 25b in 68% yield and 98:2
of CuCN 2LiCl (1 M in THF) and 5 drops of allyl bromide in
3
0.5 mL of THF. The analytical data for known compounds
match the literature data. The stereochemistry of compounds 25
were determined by NOESY-NMR experiments.
Starting Materials and Organometallic Reagents. i-PrMgCl LiCl
3
(3) is commercially available. TMP2Mg 2LiCl was prepared
3
according to the literature procedure.5f,17 The enol phosphates
13,18 15,4a 20,4a and 214b were prepared according to literature
procedures. Enol phosphate 9 was prepared as follows:
(15) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685. (b) Walker, S. D.; Barder, T. E.; Martinelli,
J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 116, 1907. (c) The use of
less active catalytic systems like Pd(PPh3)4 or Pd(dba)2/tfp did not lead to the
corresponding cross-coupling products when aryl bromides were used instead of
aryl iodides.
2-Iodocyclopent-2-enone (8) (5.20 g, 25.0 mmol) dissolved in
dry THF (30 mL) was cooled to -78 °C. L-Selectride (27.5 mL,
(17) Rohbogner, C. J.; Wagner, A. J.; Clososki, G. C.; Knochel, P. Org.
Synth. 2009, 86, 374.
(18) Hayashi, T.; Fujiwa, T.; Okamoto, Y.; Katsuro, Y.; Kumada, M.
Synthesis 1981, 1001.
(16) Vashchenko, V.; Kutulya, L.; Krivoshey, A. Synthesis 2007, 14,
2125.
4368 J. Org. Chem. Vol. 75, No. 13, 2010

Piller et al.
JOCFeatured Article
TABLE 4. Products Obtained by the Reaction of 22 with Various
Electrophiles
27.5 mmol, 1.0 M in THF) was then added dropwise. After 2 h of
stirring at -78 °C, phosphorochloridic acid diethyl ester (5.6 g,
32.5 mmol) was added, and the mixture was allowed to warm to
room temperature. After 1.5 h, the resulting mixture was
quenched with a satd aq NH4Cl solution (30 mL), extracted
with diethyl ether (3 ꢀ 50 mL), and dried over anhydrous
Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash chromatography (pentane/Et2O = 1: 1)
furnished the compound 9 (5.3 g, 17.7 mmol, 71%) as a yellow-
ish oil: 1H NMR (CDCl3, 300 MHz) δ = 4.18 (dq, J = 14.2, J =
7.1 Hz, 4 H), 2.49-2.60 (m, 4 H), 1.98-2.08 (m, 2 H), 1.34 (td,
J = 7.1 Hz, J = 1.0 Hz, 6 H); 13C NMR (CDCl3, 75 MHz) δ =
152.4 (d, J = 5.9 Hz), 74.2 (d, J = 11.1 Hz), 64.6 (d, J = 6.2 Hz,
2 C), 37.7, 30.1, 21.9, 16.0 (d, J = 6.7 Hz, 2 C); IR (film, cm-1
)
ν~ = 2982 (m), 1722 (w), 1661 (s), 1280 (vs), 1224 (m), 1031 (vs),
963 (vs), 859 (s), 553 (w); MS (EI, 70 eV) m/z 346 (Mþ, 19), 219
(61), 191 (46), 163 (100), 162 (20), 83 (45), 81 (22), 65 (28);
HRMS (EI) calcd for C9H16O4PI, 345.9831, found 345.9827.
Typical Procedures (TP). TP1: Metalation of Vinyl Phosphates.
The corresponding phosphate (1.0 mmol) in THF (2.0 mL) reacted
with freshly titrated TMP2Mg 2LiCl (1.3 equiv, 2.36 mL, 0.55 M
3
in THF) at the specified temperature and was stirred until the
metalation was complete. The completion of the metalation was
checked by GC analysis of reaction aliquots quenched with a
solution of 3 drops of CuCN 2LiCl (1 M in THF) and 5 drops of
3
allyl bromide in 0.5 mL of THF.
TP2: Transmetalation of Magnesium Reagents. To the Mg
species that was prepared according to TP2 was added ZnCl2
solution (1.0 M in THF, 1.1 mL, 1.1 equiv) at -20 °C, and the
resulting mixture was stirred for 15 min.
TP3: I/Mg Exchange on Phosphoric Acid 2-Iodocyclopent-1-
enyl Ester Diethyl Ester (9). A solution of phosphoric acid
2-iodocyclopent-1-enyl ester diethyl ester (9) (346 mg, 1.0 mmol)
in dry THF (1.0 mL) was cooled to -50 °C, i-PrMgCl LiCl
3
(0.96 mL, 1.1 mmol, 1.14 M in THF) was then added slowly, and
the resulting mixture was stirred for 5 min at this temperature.
Further functionalizations were performed as described below.
TP4: Br/Mg Exchange on 3-Bromo-1,7,7-trimethylbicyclo-
[2.2.1]hept-2-en-2-yl Diethyl Phosphate (21). To neat 21 (367
mg, 1.0 mmol) was added i-PrMgCl LiCl (0.96 mL, 1.1 mmol,
3
1.14 M in THF) at 25 °C, and the resulting mixture was stirred
for 2 h at this temperature. Further functionalizations were
performed as described below.
Experimental Procedures and Analytical Data. Diethyl 2-
(Phenylthio)cyclopent-1-en-1-yl Phosphate (11a). (2-Iodo-cyclo-
pent-1-enyl)phosphonic acid diethyl ester (9) (346 mg, 1.0 mmol)
was treated with i-PrMgCl LiCl according to TP3. The mixture
3
was cooled to -50 °C, benzenethiosulfonic acid S-phenyl ester
(300 mg, 1.2 mmol) was then added, and the resulting mixture was
allowed to stir at 25 °C for 3 h. The mixture was then quenched
with a satd aq NH4Cl solution (30 mL), extracted with diethyl
ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After fil-
tration, the solvent was evaporated in vacuo. Purification by flash
chromatography (pentane/Et2O = 1:2) furnished the compound
11a (273 mg, 0.83 mmol, 83%) as a colorless oil: 1H NMR (CDCl3,
300 MHz) δ = 7.15-7.33 (m, 5 H), 4.00 (dq, J = 14.1 Hz, J =
7.1 Hz, 4 H), 2.70-2.77 (m, 2 H), 2.29-2.38 (m, 2 H), 1.91-2.01
(m, 2H), 1.34(td, J=7.1Hz, J= 1.0 Hz, 6 H); 13CNMR(CDCl3,
75 MHz) δ = 150.6 (d, J = 6.9 Hz), 134.0, 130.0, 128.8, 126.4,
114.2 (d, J = 9.4 Hz), 64.6 (d, J = 6.2 Hz), 32.1, 31.9, 16.0 (d, J =
6.8 Hz); IR (ATR) ν~(cm-1) 2982, 1649, 1478, 1283, 1032, 985, 873,
745, 692; MS (70 eV, EI) m/z328 (73) [Mþ], 219 (100), 191 (46), 173
(40), 163 (62), 147 (17), 109 (19), 91 (17), 83 (15), 81 (20); HRMS
(EI) calcd for C15H21O4PS 328.0898, found 328.0895.
2-[(Diethylamino)methyl]cyclopent-1-en-1-yl Diethyl Phos-
phate (11b). (2-Iodocyclopent-1-enyl)phosphonic acid diethyl ester
(9) (346 mg, 1.0 mmol) was treated with i-PrMgCl LiCl according
aYield of analytically pure product. bObtained after transmetalation
c
with CuCN 2LiCl (20-100 mol %). Obtained after transmetalation
3
3
with ZnCl2 (1.1 equiv) and Pd-catalyzed cross-coupling.
to TP3. A mixture of benzotriazol-1-ylmethyldiethylamine and
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SCHEME 7. Reaction of Magnesium Reagent 22 with Various Aldehydes Leading to R,β-Unsaturated Ketones of Type 25
benzotriazol-2-ylmethyldiethylamine (245 mg, 1.2 mmol) was then
added at -50 °C, and the resulting mixture was allowed to warm to
25 °C. After addition of THF (4 mL), the mixture was stirred for an
additional 1 h at 25 °C, quenched with a satd aq NH4Clsolution(30
mL), extracted with diethyl ether (3 ꢀ 50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in
vacuo. Purification by flash chromatography (pentane/Et2O = 1:2)
furnished the compound 11b (251 mg, 0.82 mmol, 82%) as a
colorless oil: 1H NMR (C6D6, 300 MHz) δ = 3.97 (dq, J = 8.5
Hz, J= 7.1 Hz, 4 H), 3.20 (s, 2 H), 2.68-2.78 (m, 2 H), 2.46 (q, J=
7.1 Hz, 4 H), 2.29-2.40 (m, 2 H), 1.64-1.74 (m, 2 H), 1.03 (td, J =
7.1 Hz, J = 0.9 Hz, 6 H), 1.00 (t, J = 7.1 Hz, 6 H); 13C NMR
(C6D6, 75 MHz) δ = 145.8 (d, J = 7.2 Hz), 122.6 (d, J = 8.5 Hz),
63.9 (d, J = 5.8 Hz), 49.4, 47.4, 32.3, 31.1, 20.0, 16.2 (d, J = 6.4
Hz), 12.3; IR (ATR) ν~ (cm-1) 2935, 1698, 1446, 1336, 1274, 10237,
966, 907; MS (70 eV, EI) m/z 276 (100) [Mþ], 170 (24), 141 (30),
136 (20), 123 (22), 122 (34), 99 (13), 81 (17), 79 (13), 72 (18);
HRMS (EI) calcd for C14H28NO4P 305.1756, found 305.1734.
Diethyl 2-(Trimethylsilyl)cyclopent-1-en-1-yl Phosphate (11c).
(2-Iodocyclopent-1-enyl)phosphonic acid diethyl ester (9) (346mg,
evaporated in vacuo. Purification by flash chromatography
(pentane/Et2O = 1:1) furnished the compound 11d (213 mg,
0.82 mmol, 82%) as a colorless oil: 1H NMR (CDCl3, 300 MHz)
δ = 5.71 (ddt, J = 16.9 Hz, J = 10.0 Hz, J = 6.7 Hz, 1 H),
4.94-5.05 (m, 2 H), 4.00 (dq, J = 14.2 Hz, J = 7.1 Hz, 4 H),
2.81-2.83 (m, 2 H), 2.52-2.60 (m, 2 H), 2.18-2.24 (m, 2 H),
1.80-1.90 (m, 2 H), 1.32 (td, J = 7.1 Hz, J = 0.9 Hz, 6 H); 13
C
NMR (CDCl3, 75 MHz) δ= 143.0 (d, J = 7.8 Hz), 135.0, 121.5 (d,
J = 8.6 Hz), 115.6, 64.1 (d, J = 6.0 Hz), 31.4, 30.8, 30.7, 19.4, 16.0
(d, J = 6.7 Hz); IR (ATR) ν~ (cm-1) 2981, 1698, 1274, 1192, 1030,
981, 908, 819, 566; MS (70 eV, EI) m/z 260 (43) [Mþ], 231 (26), 155
(26), 127 (28), 106 (46), 105 (100), 99 (50), 91 (55), 81 (25), 79 (27);
HRMS (EI) calcd for C12H21O4P 260.1177, found 260.1197.
2-Benzoylcyclopent-1-en-1-yl Diethyl Phosphate (11e). (2-Iodo-
cyclopent-1-enyl)phosphonic acid diethyl ester (9) (346 mg, 1.0
mmol) was treated with i-PrMgCl LiCl according to TP3. The
3
solution was cooled to -50 °C, CuCN 2LiCl (1.1 mL, 1.1 mmol,
3
1.0 M in THF) and benzoyl chloride (169 mg, 1.2 mmol) were then
added, and the resulting mixture was stirred at 0 °C for 2 h. The
mixture was then quenched with a satd aq NH4Cl solution (30 mL),
extracted with diethyl ether (3 ꢀ 50 mL), and dried over anhydrous
Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash chromatography (pentane/Et2O = 1:7) furni-
shed the compound 11e (273 mg, 0.84 mmol, 84%) as a yellowish
oil: 1H NMR (CDCl3, 300 MHz) δ = 7.77 (d, J = 6.9 Hz, 2 H),
7.38-7.51 (m, 3 H), 3.67-3.85 (m, 4 H), 2.84-2.89 (m, 2 H),
2.71-2.77 (m, 2 H), 1.96-2.07 (m, 2 H), 1.13 (td, J = 7.1 Hz, J =
1.0 Hz, 6 H); 13C NMR (CDCl3, 75 MHz) δ = 193.2, 154.4 (d, J =
6.0 Hz), 138.8, 132.0, 128.9, 128.1, 121.8 (d, J = 9.0 Hz), 64.5 (d,
J = 6.4 Hz), 33.3, 30.3, 19.6, 15.8 (d, J = 7.0 Hz); IR (ATR) ν~
(cm-1) 2983, 1641, 1448, 1362, 1278, 1037, 986, 897, 724; MS
(70 eV, EI) m/z 324 (70) [Mþ], 170 (24), 169 (64), 155 (43), 142 (38),
141 (30), 128 (47), 105 (100), 81 (17), 77 (41); HRMS (EI) calcd for
C16H21O5P 324.1127, found 324.1158.
1.0 mmol) was treated with i-PrMgCl LiCl according to TP3. The
3
mixture was cooled to -50 °C, and TMSCN (109 mg, 1.2 mmol)
was added. The solution was allowed to warm to -20 °C and
stirred for 3 h at this temperature. The reaction mixture was then
quenched with a satd aq NH4Cl solution (30 mL), extracted with
diethyl ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After
filtration, the solvent was evaporated in vacuo. Purification by
flash chromatography (pentane/Et2O = 1:1) furnished the com-
pound 11c (258 mg, 0.88 mmol, 88%) as a colorless oil: 1H NMR
(CDCl3, 300 MHz) δ = 4.14 (dq, J = 14.2 Hz, J = 7.1 Hz, 4 H),
2.60-2.68 (m, 2 H), 2.27-2.35 (m, 2 H), 1.85-1.97 (m, 2 H), 1.34
(td, J = 7.1 Hz, J = 1.0 Hz, 6 H), 0.10 (s, 9 H); 13C NMR (CDCl3,
75 MHz) δ= 156.6 (d, J= 6.7 Hz), 119.8 (d, J= 10.1Hz), 64.0(d,
J= 6.0 Hz), 33.2, 32.0, 22.3, 16.1 (d, J= 6.8 Hz), 1.39; IR (ATR) ν~
(cm-1) 2982, 2957, 1635, 1249, 1034, 993, 890, 840, 756; MS (70 eV,
EI) m/z 292 (12) [Mþ], 221 (17), 203 (15), 171 (13), 155 (100), 83
(29), 75 (14); HRMS (EI) calcd for C12H25O4PSi 292.1260, found
292.1266.
Diethyl 2-(3-oxocyclohex-1-en-1-yl)cyclopent-1-en-1-yl phos-
phate (11f). (2-Iodocyclopent-1-enyl)phosphonic acid diethyl ester
(9) (346 mg, 1.0 mmol) was treated with i-PrMgCl LiCl according
3
to TP3. CuCN 2LiCl (1.1 mL, 1.1 mmol, 1.0 M in THF) was then
3
2-Allylcyclopent-1-en-1-yl Diethyl Phosphate (11d). (2-Iodo-
cyclopent-1-enyl)phosphonic acid diethyl ester (9) (346 mg, 1.0
mmol) was treated with i-PrMgCl LiCl according to TP3.
added at -30 °C, and the mixture was stirred at this temperature
for 1 h. 3-Iodocyclohex-2-enone (169 mg, 1.2 mmol) in 1 mL of
THF was then added at -30 °C, and the mixture was allowed to
warm to 0 °C and stirred for 2 h. The reaction mixture was then
quenched with a satd aq NH4Cl solution (30 mL), extracted with
diethyl ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4.
After filtration, the solvent was evaporated in vacuo. Purification
by flash chromatography (Et2O) furnished the compound 11f (223
mg, 0.71 mmol, 71%) as a colorless oil: 1HNMR(C6D6, 300 MHz)
δ = 6.07 (s, 1 H), 3.90 (dq, J = 14.4 Hz, J = 7.1 Hz, 4 H), 2.73 (t,
3
CuCN 2LiCl (1.1 mL, 1.1 mmol, 1.0 M in THF) was then
3
added, and the resulting mixture was stirred for 10 min and then
cooled to -50 °C. Allyl bromide (145 mg, 1.2 mmol) was then
added dropwise, and the mixture was stirred at 25 °C for 1 h. The
reaction mixture was then quenched with a satd aq NH4Cl
solution (30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and
dried over anhydrous Na2SO4. After filtration, the solvent was
4370 J. Org. Chem. Vol. 75, No. 13, 2010

Piller et al.
JOCFeatured Article
J = 7.0 Hz, 2 H), 2.50 (t, J = 5.7 Hz, 2 H), 2.16-2.21 (m, 2 H),
2.05-2.10 (m, 2 H), 1.54-1.65 (m, 2 H), 1.41-1.51 (m, 2 H), 0.99
(td, J = 7.1 Hz, J = 0.8 Hz, 6 H); 13C NMR (C6D6, 75 MHz) δ =
198.02, 153.4, 151.9 (d, J = 6.5 Hz), 125.9, 120.5 (d, J = 9.0 Hz),
64.4 (d, J = 5.8 Hz), 37.7, 34.0, 30.2, 27.9, 23.1, 19.2, 16.1 (d, J =
6.4 Hz); IR (ATR) ν~ (cm-1) 2982, 2944, 1665, 1625, 1278, 1188,
1032, 968, 892, 518; MS (70 eV, EI) m/z 314 (52) [Mþ], 160 (100),
159 (72), 155 (44), 145 (40), 131 (29), 127 (42), 117 (26), 99 (34), 91
(43), 81 (23), 77 (26); HRMS (EI) calcd for C15H23O5P 314.1283,
found 314.1288.
(130 mg, 0.45 mmol, 45%) as a colorless oil: 1H NMR (600 MHz,
CDCl3) δ 5.57-5.68 (m, 1 H), 5.45-5.39 (m, 1 H), 4.20-4.05 (m,
4 H), 3.32-3.26 (m, 1 H), 2.60-2.53 (m, 2 H), 2.25-2.16 (m, 2 H),
2.00-1.93 (m, 2 H), 1.89-1.66 (m, 4 H), 1.62-1.40 (m, 2 H),
1.37-1.31 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 142.1 (d, J =
7.7 Hz), 129.6, 127.8, 127.1 (d, J = 8.8 Hz), 64.1 (d, J = 6.2 Hz),
33.1, 31.5, 28.2, 27.1, 24.8, 22.0, 19.6, 16.1 (t, J = 6.7 Hz); IR
(ATR) ν~ (cm-1) 2256, 2980, 2931, 2857, 2301, 1990, 1724, 1692,
1478, 1444, 1393, 1333, 1243, 1186, 1164, 1098, 1019, 972, 904, 868,
817, 801, 748, 722, 671, 640, 617, 611; MS (70 eV, EI) m/z 300 (18)
[Mþ], 163 (6), 155 (38), 146 (100), 131 (28), 117 (22), 99 (10);
HRMS (EI) calcd for C15H25O4P 300.1490, found 300.1503.
Ethyl 4-[2-[Ddiethoxyphosphoryl)oxy]cyclopent-1-en-1-yl]benzo-
ate (11i). Cyclopent-1-en-1-yl diethyl phosphate 13 (220 mg,
1.0 mmol) reacted at -10 °C for 2 h according to TP1 and was
then transmetalated according to TP2. Pd(dba)2 (23 mg, 4 mol %),
P(2-furyl)3 (28 mg, 12 mol %), and ethyl-4-iodobenzoate (360 mg,
1.3 mmol, 1.3 equiv) were then added to the reaction mixture. The
resulting mixture was stirred at -10 °C overnight, quenched with
a satd aq NH4Cl solution (30 mL), extracted with diethyl ether
(3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After filtration,
the solvent was evaporated in vacuo. Purification by flash chro-
matography (pentane/EtOAc = 3:1) furnished the compound 11i
(210 mg, 0.58 mmol, 58%) as a yellow oil: 1H NMR (600 MHz,
CDCl3) δ 7.99 (J = 8.7 Hz, 2 H), 7.60 (d, J = 8.7 Hz, 2 H), 4.36 (q,
J = 7.2 Hz, 2 H), 4.19-4.09 (m, 4 H), 2.88-2.85 (m, 2 H),
2.75-2.71 (m, 2 H), 2.04-1.99 (m, 2 H), 1.38 (t, J = 7.0 Hz, 3 H),
1.32 (td, J = 7.0 Hz, J = 1.0 Hz, 6 H); 13C NMR (100 MHz,
CDCl3) δ 166.5, 147.1, 139.1, 129.3, 128.6, 126.7, 119.4, 64.5 (d,
J = 5.7 Hz), 60.8, 33.1, 31.1, 19.3, 16.1 (d, J = 7.2 Hz), 14.3; IR
(ATR) ν~ (cm-1) 2982, 2934, 2907, 1711, 1651, 1601, 1477, 1444,
1409, 1393, 1367, 1340, 1271, 1182, 1103, 1018, 957, 877, 855, 773,
702; MS (70 eV, EI) m/z 368 (22) [Mþ], 322 (100), 294 (63), 265
(33), 203 (11), 185 (79), 169 (26), 157 (13), 141 (51), 129 (22), 115
(50), 102 (21), 80 (24); HRMS (EI) calcd for C18H25O6P 368.1389,
found 368.1387.
Diethyl 2-[3-(Trifluoromethyl)phenyl]cyclopent-1-en-1-yl Phos-
phate (11j). Cyclopent-1-en-1-yl diethyl phosphate 13 (220 mg,
1.0 mmol) reacted at -10 °C for 2 h according to TP1 and was then
transmetalated according to TP2. Pd(dba)2 (29 mg, 5 mol %), P(2-
furyl)3 (24 mg, 10 mol %) and trifluoro-3-iodobenzene (360 mg,
1.3 mmol, 1.3 equiv) were then added to the reaction mixture. The
resulting mixture was stirred at -10 °C overnight, quenched with a
satd aq NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL), and dried over anhydrous Na2SO4. After filtration, the
solvent was evaporated in vacuo. Purification by flash chroma-
tography (pentane/EtOAc = 4:1) furnished the compound 11j
(210 mg, 0.58 mmol, 58%) as a yellow oil: 1H NMR (300 MHz,
CDCl3) δ 7.86 (s, 1 H), 7.65-7.60 (m, 1 H), 7.45-7.39 (m, 2 H),
4.19-4.09 (m, 4 H), 2.91-2.82 (m, 2 H), 2.75-2.67 (m, 2 H), 2.0
(p, J = 7.5 Hz, 2 H), 1.31 (tq, J = 7.0 Hz, J = 0.49 Hz, 6 H); 13C
NMR (75 MHz, CDCl3) δ 146.5 (d, J = 6.7 Hz) 135.4 (d, J = 1.54
Hz), 130.4 (q, J= 32.0 Hz), 130.0, 128.6, 126.1, 123.4 (dq, J= 49.2
Hz, J = 3.9 Hz), 118.8 (d, J = 9.3 Hz), 64.4 (dd, J = 18.6 Hz, J =
6.2 Hz), 33.0, 31.0, 20.9, 19.3, 16.0 (d, J = 7.0 Hz); IR (ATR) ν~
(cm-1) 2990, 2169, 2911, 2852, 1659, 1486, 1446, 1393, 1370, 1342,
1323, 1277, 1221, 1196, 1180, 1163, 1115, 1091, 1073, 1026, 968,
884, 808, 754, 701, 663, 647, 633, 610, 604; MS (70 eV, EI) m/z 364
(44) [Mþ], 316 (44), 267 (15), 190 (100), 151 (11); HRMS (EI) for
Calcd C16H20F3O4P 364.1051, found 364.1045.
tert-Butyl 4-[2-[(Diethoxyphosphoryl)oxy]cyclopent-1-en-1-yl]-
benzoate (11g). (2-Iodocyclopent-1-enyl)phosphonic acid diethyl
ester (9) (346 mg, 1.0 mmol) was treated with i-PrMgCl LiCl
3
according to TP3. ZnCl2 solution (1.1 mL, 1.1 mmol, 1.0 M in
THF) was then added, and the mixture was allowed to warm to
25 °C. Pd(dba) 2 (29 mg, 5 mol %) and P(2-furyl)3 (23 mg, 10 mol
%) dissolved in THF (2 mL) and mixed with ethyl tert-butyl
4-iodobenzoate (335 mg, 1.1 mmol) were then transferred via
cannula to the reaction mixture. The resulting mixture was stirred
at 25 °C for 2.5 h, quenched with a satd aq NH4Cl solution
(30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in
vacuo. Purification by flash chromatography (pentane/Et2O =
1:5) furnished the compound 11g (312 mg, 0.79 mmol, 79%) as a
light brown oil: 1H NMR (CDCl3, 300 MHz) δ = 7.55 (d, J = 8.7
Hz, 2 H), 7.00 (d, J = 8.7 Hz, 2 H), 4.06-4.18 (m, 4 H), 2.80-2.86
(m, 2H), 2.66-2.72 (m, 2 H), 1.91-2.04 (m, 2 H), 1.34 (s, 9H), 1.31
(td, J = 7.1 Hz, J = 1.0 Hz, 6 H); 13C NMR (CDCl3, 75 MHz)
δ = 177.0, 149.5, 144.8 (d, J = 7.2 Hz), 132.1, 127.9, 121.0, 119.4
(d, J = 9.1 Hz), 64.3 (d, J = 6.0 Hz), 39.0, 32.9, 31.3, 27.1, 19.2,
16.0 (d, J = 6.8 Hz); IR (ATR) ν~ (cm-1) 2980, 2935, 1753, 1600,
1507, 1205, 1168, 1115, 1033, 898; MS (70 eV, EI) m/z 396 (55)
[Mþ], 313 (16), 312 (100), 284 (18), 283 (35), 174 (13), 158 (31),157
(36), 57 (50); HRMS (EI) calcd for C20H 29O6P 396.1702, found
396.1679.
2-Allylcyclopent-1-en-1-yl Diethyl Phosphate (11d). Cyclo-
pent-1-en-1-yl diethyl phosphate 13 (220 mg, 1.0 mmol) reacted
at -10 °C for 2 h according to TP1 and was then transmetalated
according to TP2. CuCN 2LiCl (1 M solution in THF, 0.4 mL)
3
and allyl bromide (600 mg, 5.0 mmol) were then added dropwise,
and the reaction mixture was stirred at -20 °C for 3 h. The
resulting mixture was then quenched with a satd aq NH4Cl
solution (30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and
dried over anhydrous Na2SO4. After filtration, the solvent was
evaporated in vacuo. Purification by flash chromatography
(pentane/EtOAc 5:1) furnished the compound 11d (150 mg,
0.56 mmol, 56%) as a colorless oil: 1H NMR (300 MHz, CDCl3)
δ 5.80-5.67 (m, 1 H), 5.06-4.96 (m, 2 H), 4.15 (p, J = 7.9 Hz,
4 H), 2.84 (d, J = 5.7 Hz, 2 H), 2.60-2.55 (m, 2 H), 2.24 (s, 2 H),
1.87 (p, J = 7.9 Hz, 2 H), 1.34 (td, J = 7.1 Hz, J = 1.0 Hz, 6 H);
13C NMR (75 MHz, CDCl3) δ 143.0 (d, J = 7.7 Hz), 135.0, 121.6
(d, J = 8.6 Hz), 115.7, 64.1 (d, J = 6.1 Hz), 31.5, 30.7, 19.5, 16.1
(d, J = 6.1 Hz); IR (ATR) ν~ (cm-1) 2976, 2917, 2851, 1698,
1444, 1382, 1350, 1337, 1274, 1191, 1166, 1118, 1061, 1024, 979,
964, 907, 872, 819, 802, 753, 663, 566; MS (70 eV, EI) m/z 260
(58) [Mþ], 231 (54), 203 (29), 106 (100), 79 (27); HRMS (EI)
calcd for C12H21O4P 260.1177, found 260.1183.
2-Cyclohex-2-en-1-ylcyclopent-1-en-1-yl Diethyl Phosphate
(11h). Cyclopent-1-en-1-yl diethyl phosphate 13 (220 mg, 1.0
mmol) reacted at -10 °C for 2 h according to TP1 and was then
transmetalated according to TP2. CuCN 2LiCl (1 M solution in
3-Allylbicyclo[2.2.1]hept-2-en-2-yl Diethyl Phosphate (17a).
The bicyclic enol phosphate 15 (250 mg, 1.0 mmol) reacted at
25 °C for 30 min according to TP1 and was then transmetalated
3
THF, 0.4 mL) and 3-bromocyclohexene (800 mg, 5.0 mmol) were
then added dropwise, and the reaction mixture was stirred at
-20 °C for 3 h. The resulting mixture was then quenched with a
satd aq NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL), and dried over anhydrous Na2SO4. After filtration, the
solvent was evaporated in vacuo. Purification by flash chroma-
tography (pentane/EtOAc = 4:1) furnished the compound 11h
according to TP2. CuCN 2LiCl (1 M solution in THF, 0.4 mL)
3
and allyl bromide (600 mg, 5.0 mmol) were then added dropwise,
and the reaction mixture was stirred at 0 °C for 1 h. The resulting
mixture was then quenched with a satd aq NH4Cl solution
(30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and dried over
J. Org. Chem. Vol. 75, No. 13, 2010 4371

Piller et al.
JOCFeatured Article
anhydrous Na2SO4. After filtration, the solvent was evaporated
in vacuo. Purification by flash chromatography (pentane/
EtOAc = 2:1) furnished the compound 17a (260 mg, 0.96 mmol,
96%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
5.82-5.69 (m, 1 H), 5.08-4.94 (m, 2 H), 4.19-4.09 (m, 4 H),
3.0 (s, 1 H), 2.93-2.86 (m, 1 H), 2.74-2.60 (m, 2 H), 1.74-1.61
(m, 2 H), 1.54-1.48 (m, 1 H), 1.46-1.38 (m, 1 H), 1.33 (td, J =
7.1 Hz, J = 0.98 Hz, 6 H), 1.15-1.09 (m, 1 H), 1.04 (td, J = 8.0
Hz, J = 1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 149.0 (d,
J = 7.2 Hz), 135.4, 124.8 (d, J = 8.5 Hz), 115.5, 64.2 (d, J = 3.6
Hz), 46.1, 43.6 (d, J = 1.0 Hz), 29.1 (d, J = 1.3 Hz), 26.0 (d, J =
10.6 Hz), 16.1 (d, J = 7.0 Hz); IR (ATR) ν~ (cm-1) 2977, 2874,
1732, 1674, 1639, 1475, 1445, 1394, 1370, 1334, 1270, 1219, 1204,
1160, 1097, 1026, 986, 950, 908, 868, 818, 762; MS (70 eV, EI)
m/z 286 (60) [Mþ], 258 (100), 155 (5), 104 (9), 91 (1); HRMS (EI)
calcd for C14H23O4P 286.1334, found 286.1307.
1.3 mmol, 1.3 equiv) were then added to the reaction mixture. The
resulting mixture was stirred at 25 °C for 2 h, quenched with a satd
aq NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL), and dried over anhydrous Na2SO4. After filtration, the
solvent was evaporated in vacuo. Purification by flash chroma-
tography (pentane/EtOAc = 1:1) furnished the compound 17d
(300 mg, 0.75 mmol, 75%) as a yellowish oil: 1H NMR (300 MHz,
CDCl3) δ 7.96 (d, J = 8.6 Hz, 2 H), 7.53 (d, J = 8.6 Hz, 2 H), 4.34
(q, J = 7.3 Hz, 2 H), 4.25-4.06 (m, 4 H), 3.32 (d, J = 9.7 Hz, 2 H),
1.93-1.82 (m, 2 H), 1.72-1.67 (m 1 H), 1.62-1.50 (m, 1 H),
1.39-1.30 (m, 8 H), 1.26-1.16 (m, 3 H); 13C NMR (75 MHz,
CDCl3) δ 166.5, 152.6 (d, J = 6.5 Hz), 137.9 (d, J = 1.5 Hz),
129.5, 127.7, 126.0, 123.8 (d, J = 9.5Hz), 64.5 (t, J = 5.9 Hz), 60.7
(d, J = 32.2 Hz), 45.4 (d, J = 7.5 Hz), 26.5 (d, J = 29 Hz), 21.0,
16.0 (q, J = 4.4 Hz), 14.3 (d, J = 11.6 Hz); IR (ATR) ν~ (cm-1
)
2979, 2873, 1711, 1628, 1605, 1562, 1508, 1476, 1446, 1412,
1393, 1367, 1345, 1270, 1213, 1183, 1166, 1103, 1050, 1020, 969,
950, 916, 856, 818, 799, 779, 761, 703; MS (70 eV, EI) m/z 394
(45) [Mþ], 366 (100), 320 (40), 292 (26), 264 (10), 230 (7), 184 (6),
80 (5); HRMS (EI) calcd for C20H27O6P 394.1545, found
394.1549.
3-Benzoylbicyclo[2.2.1]hept-2-en-2-yl Diethyl Phosphate (17b).
The bicyclic enol phosphate 15 (250 mg, 1.0 mmol) reacted at 25 °C
for 30 min according to TP1. The resulting mixture was cooled to
-20 °C, CuCN 2LiCl (1 M solution in THF, 1.1 mL) was added,
3
and the reaction mixture was stirred at this temperature for 30 min.
Benzoyl chloride (350 mg, 2.5 mmol) was then added, and the
mixture was allowed to warm fast to 25 °C for 1 h. The resulting
mixture was then quenched with a satd aq NH4Cl solution
(30 mL), extracted with diethyl ether (3 ꢀ 50 mL) and aq NH3,
and dried over anhydrous Na2SO4. After filtration, the solvent was
evaporated in vacuo. Purification by flash chromatography
(pentane/EtOAc = 2:1) furnished the compound 17b (260 mg,
0.75 mmol, 75%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ
7.76-7.72 (m, 2 H), 7.49-7.35 (m, 3 H), 3.86-3.71 (m, 4 H), 3.36
(s, 2 H), 1.98-1.92 (m, 2 H), 1.77-1.70 (m, 1 H), 1.60-1.46 (m, 2
H), 1.26-1.20 (m, 1 H), 1.18-1.10 (m, 6 H); 13C NMR (75 MHz,
CDCl3) δ 191.7, 160.3 (J = 5.7 Hz), 139.3, 131.8, 128.9, 128.0,
125.6 (d, J = 9.0 Hz), 64.6 (d, J = 6.5 Hz), 45.9, 44.8 (d, J = 1.3
Hz), 43.3, 26.2 (d, J = 31.2 Hz), 15.8 (d, J = 7.0 Hz); IR (ATR) ν~
(cm-1) 2981, 2877, 1633, 1598, 1578, 1476, 1447, 1365, 1282, 1268,
1220, 1204, 1168, 1115, 1024, 992, 949, 933, 892, 846, 819, 802, 787,
774, 749, 714, 694, 675; MS (70 eV, EI) m/z 350 (46) [Mþ], 168
(100), 105 (37), 77 (25); HRMS (EI) calcd for C18H23O5P
350.1283, found 350.1268.
Diethyl 3-(Methylthio)bicyclo[2.2.1]hept-2-en-2-yl Phosphate
(17c). The bicyclic enol phosphate 15 (250 mg, 1.0 mmol) reacted
at 25 °C for 30 min according to TP1. Benzenethiosulfonic acid
S-methyl ester (570 mg, 3.0 mmol) was then added dropwise,
and the reaction mixture was warmed to 30 °C for 3 h. The
resulting mixture was then quenched with a satd aq NH4Cl
solution (30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and
dried over anhydrous Na2SO4. After filtration, the solvent was
evaporated in vacuo. Purification by flash chromatography
(pentane/EtOAc = 4:1) furnished the compound 17c (160 mg,
0.73 mmol, 73%) as a yellowish oil: 1H NMR (300 MHz,
CDCl3) δ 4.24-4.12 (m, 4 H), 3.11 (s, 1 H), 2.94 (s, 1 H), 2.24
(s, 3 H), 1.79-1.65 (m, 2 H), 1.54-1.42 (m, 2 H), 1.34 (tp, J =
7.1 Hz, J = 0.97 Hz, 6 H), 1.29-1.19 (m, 1 H), 1.12-1.08 (m,
1 H); 13C NMR (75 MHz, CDCl3) δ 151.5 (d, J = 6.4 Hz), 119.9
(d, J = 9.5 Hz), 64.4 (t, J = 6.2 Hz), 44.5 (d, J = 3.6 Hz), 26.3 (d,
J = 1.0 Hz), 26.0 (d, J = 1.8 Hz), 16.1 (d, J = 4.9 Hz), 15.1; IR
(ATR) ν~ (cm-1) 2979, 2925, 2872, 1619, 1478, 1444, 1393, 1370,
1315, 1276, 1216, 1198, 1155, 1124, 1098, 1054, 1023, 965, 947,
936, 917, 850, 818, 796, 758, 734; MS (70 eV, EI) m/z 292 (29)
[Mþ], 277 (37), 264 (29), 236 (67), 218 (22), 208 (55), 123 (46), 110
(100); HRMS (EI) calcd for C12H21O4PS 292.0898, found
292.0889.
3-Allyl-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl Diethyl Phos-
phate (23a). Method A. The bicyclic enol phosphate 20 (288 mg,
1.0 mmol) reacted at 25 °C for 30 min according to TP1 and was
then transmetalated according to TP2. CuCN 2LiCl (1 M solu-
3
tion in THF, 0.2 mL) and allyl bromide (605 mg, 5.0 mmol) were
then added dropwise, and the reaction mixture was allowed to
warm slowly to 25 °C overnight. The resulting mixture was then
quenched with a satd aq NH4Cl solution (30 mL), extracted with
diethyl ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4.
After filtration, the solvent was evaporated in vacuo. Purification
by flash chromatography (pentane/EtOAc = 6:1) furnished the
compound 23a (270 mg, 0.82 mmol, 82%) as a colorless oil.
Method B. The bicyclic enol phosphate 21 (367 mg, 1.0 mmol)
reacted at 25 °C for 2 h according to TP4. CuCN 2LiCl (1 M
3
solution in THF, 0.2 mL) and allyl bromide (132 mg, 1.1 mmol)
were then added dropwise, and the reaction mixture was stirred
for 1 h at 25 °C. The resulting mixture was then quenched with a
satd aq NH4Cl solution (30 mL), extracted with diethyl ether
(3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After filtration,
the solvent was evaporated in vacuo. Purification by flash
chromatography (pentane/ EtOAc = 6:1) furnished the com-
pound 23a (203 mg, 0.62 mmol, 62%) as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 5.83-5.69 (m, 1 H), 5.10-4.97 (m, 2 H),
4.20-4.10 (m, 4 H), 3.07-2.99 (m, 1 H), 2.79-2.69 (m, 1 H),
2.18 (d, J = 3.7 Hz, 1 H), 1.85-1.74 (m, 1 H), 1.62-1.53 (m, 1
H), 1.47-1.39 (m, 1 H), 1.34 (tq, J = 7.1 Hz, J = 1.0 Hz, J =
0.51 Hz, 6 H), 1.11-1.03 (m, 1 H), 1.00 (s, 3 H), 0.89 (s, 3 H), 0.72
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 135.4, 124.6 (d, J = 6.4
Hz), 115.8, 64.2, 55.1, 54.4, 52.4 (d, J = 1.4 Hz), 32.5 (d, J = 1.7
Hz), 30.2 (d, J = 1.7 Hz), 25.4 (d, J = 5.6 Hz), 19.7 (d, J = 28.8
Hz), 16.2 (d, J = 6.9 Hz), 10.2; MS (70 eV, EI) m/z 328 (2) [Mþ],
111 (54), 97 (70), 85 (44), 83 (67), 71 (65), 69 (69), 57 (100), 55
(55), 43 (50); IR (ATR) ν~ (cm-1) 2954, 2873, 1672, 1639, 1476,
1444, 1388, 1368, 1319, 1271, 1211, 1167, 1133, 1054, 1028, 1008,
977, 928, 858, 820, 756, 647, 603; HRMS (EI) calcd for C17H29-
O4P 328.1803, found 328.1784.
3-Cyclohex-2-en-1-yl-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl
Diethyl Phosphate (23b). The bicyclic enol phosphate 20 (288 mg,
1.0 mmol) reacted at 25 °C for 30 min according to TP1 and was
then transmetalated according to TP2. CuCN 2LiCl (1 M solution
3
in THF, 0.2 mL) and 3-bromocyclohexene (805 mg, 5.0 mmol)
were then added dropwise, and the reaction mixture was allowed to
warm slowly to 25 °C overnight. The resulting mixture was then
quenched with a satd aq NH4Cl solution (30 mL), extracted with
diethyl ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4.
After filtration, the solvent was evaporated in vacuo. Purification
by flash chromatography (pentane/EtOAc = 7:1) furnished the
Ethyl 4-[3-[(Diethoxyphosphoryl)oxy]bicyclo[2.2.1]hept-2-en-
2-yl]benzoate (17d). The bicyclic enol phosphate 15 (250 mg,
1.0 mmol) reacted at 25 °C for 30 min according to TP1 and was
then transmetalated according to TP2. Pd(dba)2 (24 mg, 4 mol %),
P(2-furyl)3 (28 mg, 12 mol %), and ethyl-4-iodobenzoate (360 mg,
4372 J. Org. Chem. Vol. 75, No. 13, 2010

Piller et al.
JOCFeatured Article
1
compound 23b (313 mg, 0.85 mmol, 85%) as a colorless oil: H
NMR (300 MHz, CDCl3) δ 5.77-5.66 (m, 1 H), 5.52-5.41 (m, 1
H), 4.21-4.08 (m, 4 H), 3.43-3.34 (m, 1 H), 2.24-2.19 (m, 1 H),
2.02-1.95 (m, 2 H), 1.89-1.71 (m, 3 H), 1.63-1.39 (m, 5 H), 1.34
(tq, J = 7.0 Hz, J = 0.97 Hz, 5 H), 1.18-1.09 (m, 1 H), 1.0 (s, 3 H),
0.89 (s, 3 H), 0.71 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 148.1 (d,
J = 11.5 Hz), 129.9 (d, J = 6.7 Hz), 128.8 (d, J = 2.0 Hz), 127.6,
64.1 (t, J = 6.5 Hz), 55.6, 54.2 (d, J = 1.7 Hz), 50.6 (d J = 1.4 Hz),
32.7 (d J = 1.7 Hz), 31.9 (d,J = 1.7 Hz), 27.6 (d, J = 2.5 Hz), 26.3
(d J = 3.7 Hz), 24.8, 21.7, 19.7, 19.4, 16.2 (d, J = 7.0 Hz), 10.2; MS
(70 eV, EI) m/z 368 (5) [Mþ], 214 (67), 199 (100), 186 (49), 171 (40),
155 (22), 145 (17), 129 (9), 115 (4), 105 (7), 91 (7); IR (ATR) ν~
(cm-1) 2931, 1670, 1476, 1444, 1386, 1366, 1271, 1212, 1166, 1126,
1054, 1028, 1009, 961, 929, 896, 825, 803, 751, 721, 686; HRMS
(EI) calcd for C20H33O4P 368.2116, found 368.2088.
J = 1.0 Hz, 1 H), 7.16 (dd, J = 3.7 Hz, J = 0.73 Hz, 1 H), 6.5 (q,
J = 2.0 Hz, 1 H), 4.05-3.91 (m, 4 H), 2.84 (d, J = 3.7 Hz, 1 H),
2.07-1.97 (m, 2 H), 1.80-1.62 (m, 2 H), 1.52-1.44 (m, 1 H),
1.27-1.15 (m, 5 H), 1.11 (s, 3 H), 0.98 (s, 3 H), 0.82 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 178.4 (d, J = 2.6 Hz), 159.8 (d, J =
12.4 Hz), 152.9, 146.0, 127.2 (d, J = 6.2 Hz), 118.0, 111.9, 64.7 (t,
J = 6.7 Hz), 56.6 (d, J = 2.1 Hz), 55.6, 52.7 (d, J = 1.0 Hz), 31.2
(d, J = 2.1 Hz), 26.0 (d, J = 3.1 Hz), 19.2 (d, J = 11.3 Hz), 16.0
(d, J = 1.6 Hz), 9.9; IR (ATR) ν~ (cm-1) 2961, 1634, 1565, 1466,
1392, 1336, 1315, 1276, 1213, 1164, 1131, 1024, 976, 918, 875,
824, 800, 754, 683; MS (70 eV, EI) m/z 382 (78) [Mþ], 354 (33),
228 (56), 213 (67), 200 (81), 185 (45), 172 (30), 95 (100); HRMS
(EI) calcd for C19H27O6P 382.1545, found 382.1541.
Ethyl 3-[(Diethoxyphosphoryl)oxy]-4,7,7-trimethylbicyclo[2.2.1]-
hept-2-ene-2-carboxylate (23e). The bicyclic enol phosphate 21
(367 mg, 1.0 mmol) reacted at 25 °C for 2 h according to TP4.
The reaction mixture was cooled to -20 °C, ethyl cyanoformate
(109 mg, 1.1 mmol) was added, and the reaction mixture was
slowly warmed to 25 °C. The resulting mixture was then quenched
with a satd aq NH4Cl solution (30 mL), extracted with diethyl
ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After
filtration, the solvent was evaporated in vacuo. Purification by
flash chromatography (pentane/EtOAc = 3:1) furnished the
compound 23e (260 mg, 0.72 mmol, 72%) as a yellow oil: 1HNMR
(CDCl3, 600 MHz) δ = 4.26-4.14 (m, 6H), 2.70 (d, J = 3.5 Hz,
1H), 1.95-1.90 (m, 1H), 1.68-1.64 (m, 1H), 1.53-1.49 (m, 1H),
1.34 (td, J = 7.1 Hz, J = 1.1 Hz, 6H), 1.28 (t, J = 7.1 Hz, 3H),
1.26-1.22 (m, 1H), 1.07 (s, 3H), 0.91 (s, 3H), 0.77 (s, 3H); 13C
NMR (CDCl3, 150 MHz) δ = 163.6, 162.6 (d, J = 11.2 Hz), 120.0
(d, J = 6.7 Hz), 64.6, 59.9, 56.6, 55.3, 50.9, 31.3 (d, J = 2.2 Hz),
3-Benzoyl-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl Diethyl
Phosphate (23c). Method A. The bicyclic enol phosphate 20
(288 mg, 1.0 mmol) reacted at 25 °C for 30 min after TP1. The
resulting mixture was cooled to -20 °C, CuCN 2LiCl (1 M
3
solution in THF, 1.1 mL) was added, and the reaction mixture
was stirred at this temperature for 30 min. Benzoyl chloride (351
mg, 2.5 mmol) was then added, and the mixture was allowed to
warm fast to 25 °C for 1 h. The resulting mixture was then
quenched with a satd aq NH4Cl solution (30 mL), extracted with
diethyl ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4.
After filtration, the solvent was evaporated in vacuo. Purifica-
tion by flash chromatography (pentane/EtOAc = 2: 1) furn-
ished the compound 23c (332 mg, 0.82 mmol, 82%) as a yellow
oil.
Method B. The bicyclic enol phosphate 21 (367 mg, 1.0 mmol)
reacted at 25 °C for 2 h according to TP4. The reaction mixture
was cooled to -20 °C, CuCN 2LiCl (1 M solution in THF,
25.6, 19.4, 19.1, 16.1 (d, J = 7.3 Hz), 14.3, 9.8; IR (ATR) ν~ (cm-1
)
2978, 1703, 1635, 1392, 13709, 1339, 1275, 1246, 1186, 1025, 921;
MS (70 eV, EI) m/z 360 (10) [Mþ], 332 (14), 314 (95), 286 (82), 258
(37), 230 (38), 178 (100); HRMS (EI) calcd for C17H29O6P
360.1702, found 360.1708.
3
0.2 mL) was added, and the reaction mixture was stirred at this
temperature for 30 min. Benzoyl chloride (155 mg, 1.1 mmol)
was then added, and the mixture was allowed to warm to 25 °C
overnight. The resulting mixture was then quenched with a satd
aq NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL), and dried over anhydrous Na2SO4. After filtration, the
solvent was evaporated in vacuo. Purification by flash chroma-
tography (pentane/EtOAc = 2:1) furnished the compound 23c
(263 mg, 0.67 mmol, 67%) as a yellow oil: 1H NMR (300 MHz,
CDCl3) δ 7.83-7.79 (m, 2 H), 7.50-7.37 (m, 3 H), 3.76-3.53 (m,
4 H), 2.82 (d, J = 3.4 Hz, 1 H), 2.06-1.95 (m, 1 H), 1.77-1.62
(m, 2 H), 1.49-1.41 (m, 1 H), 1.09 (m, 12 H), 0.83 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 191.8 (d, J = 2.6 Hz), 158.5 (d, J =
12.4 Hz), 139.0, 132.0, 129.1, 128.0, 64.3 (t, J = 6.7 Hz), 56.8,
55.1, 52.8, 31.5 (d, J = 2.1 Hz), 26.0 (d, J = 3.1 Hz), 19.4 (d, J =
6.7 Hz), 15.9 (q, J = 3.1 Hz), 9.8; IR (ATR) ν~ (cm-1) 2964, 2879,
1638, 1614, 1578, 1478, 1450, 1341, 1317, 1283, 1276, 1251, 1204,
1168, 1127, 1107, 1032, 1010, 977, 921, 894, 880, 827, 820, 775,
723, 703, 694, 657, 621; MS (70 eV, EI) m/z 392 (32) [Mþ], 238
(23), 223 (34), 210 (33), 195 (38), 167 (13), 155 (13), 105 (100), 91
(9), 77 (34); HRMS (EI) calcd for C21H29O5P 392.1753, found
392.1746.
Diethyl 1,7,7-Trimethyl-3-(methylthio)bicyclo[2.2.1]hept-2-
en-2-yl Phosphate (23f). The bicyclic enol phosphate 20 (288
mg, 1.0 mmol) reacted at 25 °C for 30 min according to TP1.
Benzenethiosulfonic acid S-methyl ester (377 mg, 2.0 mmol) was
then added dropwise, and the reaction mixture was warmed to
30 °C for 2 h. The resulting mixture was then quenched with a
satd aq NH4Cl solution (30 mL), extracted with diethyl ether
(3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After filtration,
the solvent was evaporated in vacuo. Purification by flash
chromatography (pentane/EtOAc = 4:1) furnished the com-
pound 23f (246 mg, 0.73 mmol, 73%) as a yellow oil: 1H NMR
(300 MHz, CDCl3) δ 4.25-4.10 (m, 4 H), 2.44 (d, J = 3.7 Hz, 1
H), 2.20 (s, 3 H), 1.88-1.82 (m, 1 H), 1.65-1.60 (m, 1 H),
1.52-1.48 (m, 1 H), 1.37-1.32 (m, 6 H), 1.28-1.18 (m, 1 H),
1.03 (s, 3 H), 0.93 (s, 3 H), 0.76 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 152.3 (d, J = 11.9 Hz), 119.5 (d, J = 7.7 Hz), 64.2 (t,
J = 6.2 Hz), 55.5 (d, J = 1.6 Hz), 53.9, 53.5, 32.3 (d, J = 2.1 Hz),
25.3 (d, J = 3.6 Hz), 19.3 (d, J = 57 Hz), 18.9, 15.9 (d, J = 8.8
Hz), 14.6 (d, J = 1.6 Hz), 9.90; IR (ATR) ν~ (cm-1) 2954, 2872,
1623, 1476, 1442, 1388, 1367, 1314, 1273, 1204, 1166, 1133, 1097,
1053, 1026, 1003, 959, 917, 822, 764, 697, 652; MS (70 eV, EI)
m/z 334 (24) [Mþ], 319 (100), 165 (88), 152 (98), 105 (32), 81 (11),
55 (21); HRMS (EI) calcd for C15H27O4PS 334.1368, found
334.1372.
Diethyl 3-(2-Furoyl)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-
yl Phosphate (23d). The bicyclic enol phosphate 20 (288 mg, 1.0
mmol) reacted at 25 °C for 30 min according to TP1. The
resulting mixture was cooled to -20 °C, CuCN 2LiCl (1 M
3
solution in THF, 1.1 mL) was added, and the reaction mixture
was stirred at this temperature for 30 min. 2-Furoyl chloride
(326 mg, 2.5 mmol) was then added, and the mixture was
allowed to warm fast to 25 °C for 1 h. The resulting mixture
was then quenched with a satd aq NH4Cl solution (30 mL),
extracted with diethyl ether (3 ꢀ 50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated
in vacuo. Purification by flash chromatography (pentane/
EtOAc = 2:1) furnished the compound 23d (285 mg, 0.74 mmol,
74%) as a yellowish oil: 1H NMR (300 MHz, CDCl3) δ 7.57 (q,
Diethyl 1,7,7-Trimethyl-3-(phenylthio)bicyclo[2.2.1]hept-2-en-2-
yl Phosphate (23g). The bicyclic enol phosphate 21 (367 mg,
1.0 mmol) reacted at 25 °C for 2 h according to TP4. The reaction
mixture was cooled to -20 °C, benzenethiosulfonic acid S-phenyl
ester (275 mg, 1.1 mmol) was added, and the reaction mixture was
slowly warmed to 25 °C. The resulting mixture was then quenched
with a satd aq NH4Cl solution (30 mL), extracted with diethyl
ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After
filtration, the solvent was evaporated in vacuo. Purification by
J. Org. Chem. Vol. 75, No. 13, 2010 4373

Piller et al.
JOCFeatured Article
flash chromatography (pentane/Et2O = 3:1) furnished the com-
pound 23g (257 mg, 0.65 mmol, 65%) as a colorless oil: 1H NMR
(CDCl3, 300 MHz) δ = 7.40-7.37 (m, 2H), 7.28-7.15 (m, 3H),
4.26-4.16 (m, 4H), 2.19 (d, J = 3.5 Hz, 1H), 1.81-1.71 (m, 1H),
1.67-1.59 (m, 1H), 1.53-1.45 (m, 1H), 1.36-1.30 (m, 6H),
1.25-1.16 (m, 1H), 1.07 (s, 3H), 0.99 (s, 3H), 0.70 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ = 155.1 (d, J = 11.1 Hz), 134.9, 130.7,
128.7, 126.5, 117.7 (d, J = 7.6 Hz), 64.5, 55.99, 54.2, 53.2, 32.9,
25.8, 19.4, 16.0 (d, J = 7.1 Hz), 10.0; IR (ATR) ν~ (cm-1) 2958,
16919, 1477, 1440, 1280, 1133, 1034, 965, 823; MS (70 eV, EI) m/z
396 (75) [Mþ], 368 (71), 319 (80), 287 (87), 214 (93), 105 (100);
HRMS (EI) for C20H29O4PS 396.1524, found 396.1532.
and was then transmetalated according to TP2. Pd(OAc)2 (4.5
mg, 2 mol %), S-Phos (16.5 mg, 4 mol %), and 3-bromoanisole
(281 mg, 1.5 mmol) were then added to the reaction mixture. The
resulting mixture was stirred at 25 °C overnight, quenched with a
satd aq NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL), and dried over anhydrous Na2SO4. After filtration, the
solvent was evaporated in vacuo. Purification by flash chroma-
tography (pentane/EtOAc = 3:1) furnished the compound 23j
(273 mg, 0.69 mmol, 69%) as a yellowish oil: 1H NMR (CDCl3,
600 MHz) δ = 7.21 (t, J = 7.9 Hz, 1H), 7-07-7.02 (m, 2H), 6.73
(dd, J = 7.9Hz, J = 2.2Hz, 1H), 4.11-3.90 (m, 4H), 3.81 (s, 3H),
2.65 (d, J = 3.7 Hz, 1H), 2.13 (brs, 1H), 1.99-1.94 (m, 1H), 1.70
(t, J = 6.3 Hz, 2H), 1.35-1.27 (m, 1H), 1.22 (td, J = 7.2 Hz, J =
1.0 Hz, 3H), 1.15 (td, J = 7.2 Hz, J = 1.0 Hz, 3H), 1.13 (s, 3H),
0.97 (s, 3H), 0.81 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ =
159.4, 150.7 (d, J = 12.0 Hz), 135.7 (d, J = 2.8), 129.0, 126.3 (d,
J = 7.6 Hz), 119.4, 112.4, 112.2, 64.2, 55.7, 55.5, 55.2, 53.5, 32.4,
25.8 (d, J = 3.7 Hz), 19.5 (d, J = 43.8 Hz), 15.9, 10.3; IR (ATR) ν~
(cm-1) 2953, 1636, 1597, 1483, 1271, 1161, 1129, 1025, 1003, 960,
922, 875, 784, 686; MS(70eV, EI) m/z 394(22) [Mþ], 240(30), 225
(33), 212 (100), 197 (17); HRMS (EI) calcd for C21H31O5P
394.1909, found 394.1908
Ethyl 4-[3-[(Diethoxyphosphoryl)oxy]-4,7,7-trimethylbicyclo-
[2.2.1]hept-2-en-2-yl]benzoate (23h). The bicyclic enol phosphate
20 (288 mg, 1.0 mmol) reacted at 25 °C for 30 min according to
TP1 and was then transmetalated according to TP2. Pd(dba)2
(11.3 mg, 2 mol %), P(2-furyl)3 (9.3 mg, 4 mol %), and ethyl-4-
iodobenzoate (359 mg, 1.3 mmol) were then added to the reaction
mixture. The resulting mixture was stirred at 25 °C for 9 h,
quenched with a satd aq NH4Cl solution (30 mL), extracted with
diethyl ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4.
After filtration, the solvent was evaporated in vacuo. Purification
by flash chromatography (pentane/EtOAc = 6: 1) furnished the
4-[(E)-(4,7,7-Trimethyl-3-oxobicyclo[2.2.1]hept-2-ylidene)methyl]-
benzonitrile (25a).The bicyclic enol phosphate 21 (367 mg, 1.0 mmol)
reacted at 25 °C for 2 h according to TP4. The reaction mixture was
cooled to -20 °C, 4-cyanobenzaldehyde (144 mg, 1.1 mmol) was
added, and the reaction mixture was slowly warmed to 25 °C. The
resulting mixture was then quenched with a satd aq NH4Cl solution
(30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in
vacuo. Purification by flash chromatography (pentane/Et2O = 3:1)
furnished the compound 25a (191 mg, 0.72 mmol, 72%) as a
1
compound 23h (326 mg, 0.74 mmol, 74%) as a yellow oil: H
NMR (300 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 2 H), 7.52 (d, J =
8.1 Hz, 2 H), 4.35 (q, J = 7.1 Hz, 2 H), 4.15-3.87 (m, 4 H), 2.69
(d, J = 3.7 Hz, 1 H), 2.06-1.95 (m, 1 H), 1.73 (t, J = 6.1 Hz, 2 H),
1.38 (t, J = 7.1 Hz, 3 H), 1.34-1.28 (m, 1 H), 1.24 (td, J = 7.1 Hz,
J = 1.2 Hz, 3 H), 1.14 (s, 3 H), 1.13 (td, J = 7.1 Hz, J = 1.2 Hz,
3 H), 0.96 (s, 3 H), 0.83 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
166.5, 152.6 (d, J = 11.9 Hz), 139.0 (d, J = 2.5 Hz), 129.4, 128.0,
126.6 (d, J = 1.1 Hz), 126.1 (d, J = 7.7 Hz), 64.3, 60.8, 56.0 (d,
J = 20.5 Hz), 53.3, 32.3 (d, J = 1.9 Hz), 25.8 (d, J = 3.6 Hz), 19.6
(d, J = 28.5 Hz), 16.0 (t, J = 6.6 Hz), 14.3, 10.2; IR (ATR) ν~
(cm-1) 2975, 2917, 2872, 1716, 1635, 1607, 1445, 1368, 1321,
1271, 1180, 1105, 1028, 1003, 980, 930, 857, 826, 763, 712; MS (70
eV, EI) m/z 436 [Mþ] (16), 408 (12), 390 (13), 363 (22), 254 (100),
282 (20), 214 (13), 209 (29), 181 (16); HRMS (EI) calcd for
C23H33O6P 436.2015, found 436.2005.
3-(4-Cyanophenyl)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl
Diethyl Phosphate (23i). The bicyclic enol phosphate 20 (288 mg,
1.0 mmol) reacted at 25 °C for 30 min according to TP1 and
was then transmetalated according to TP2. Pd(dba)2 (11.3 mg, 2
mol %), P(2-furyl)3 (9.3 mg, 4 mol %), and 4-iodobenzonitrile
(298 mg, 1.3 mmol) were then added to the reaction mixture. The
resulting mixture was stirred at 25 °C overnight, quenched with
a satd aq NH4Cl solution (30 mL), extracted with diethyl ether
(3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After filtration,
the solvent was evaporated in vacuo. Purification by flash
chromatography (pentane/EtOAc = 3:1) furnished the com-
pound 23i (227 mg, 0.58 mmol, 58%) as a yellowish oil: 1H NMR
(300 MHz, CDCl3) δ 7.58-7.52 (m, 4 H), 4.16-3.87 (m, 4 H),
2.66 (d, J = 3.64 Hz, 1 H), 2.05-1.95 (m, 1 H), 1.79-1.65 (m,
2 H), 1.36-1.23 (m, 1 H), 1.25 (td, J = 7.1 Hz, J = 1.2 Hz, 3 H),
1.14 (td, J = 7.1 Hz, J = 1.2 Hz, 3 H), 1.13 (s, 3 H), 0.94 (s, 3 H),
0.82 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 153.8 (d, J = 12.1
Hz), 139.0 (d, J = 3.1 Hz), 131.9, 127.2 (d, J = 1.4 Hz), 125.3 (d,
J = 7.9 Hz), 119.2, 109.3, 64.4 (t, J = 4.5 Hz), 56.2 (d, J = 1.4
Hz), 55.8, 53.1, 32.3 (d, J = 2.3 Hz), 25.6 (d, J = 3.6 Hz), 19.3 (d,
J = 47.0 Hz), 16.0 (q, J = 7.0 Hz), 10.2; IR (ATR) ν~ (cm-1) 2976,
2927, 2854, 2227, 1633, 1605, 1444, 1381, 1351, 1277, 1118, 1032,
1004, 963, 913, 844, 750; MS (70 eV, EI) m/z 389 (12) [Mþ], 235
(20), 220 (23), 207 (100), 192 (16), 167 (19), 155 (17), 140 (3), 127
(6); HRMS (EI) calcd for C21H28NO4P 389.1756, found
389.1742.
1
colorless oil: H NMR (CDCl3, 300 MHz) δ = 7.65 (d, J = 8.4
Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 3.03 (d, J = 4.5 Hz,
2H), 2.25-2.13 (m, 1H), 1.86-1.76 (m, 1H), 1.63-1.47 (m, 2H),
1.02 (s, 3H), 1.00 (s, 3H), 0.76 (s, 3H); 13C NMR (CDCl3, 75 MHz)
δ = 207.4, 145.1, 140.3, 132.3, 130.09, 125.1, 118.6, 111.8, 57.1, 49.2,
46.6, 30.4, 25.9, 20.6, 18.2, 9.2; IR (ATR) ν~ (cm-1) 3436, 2959, 2228,
1724, 1648, 1504, 1324, 1295, 1064, 1016, 837; MS (70 eV, EI) m/z
265 (100) [Mþ], 250 (58), 222 (57), 183 (59), 154 (54); HRMS (EI)
for C18H19NO: (265.1467) 265.1492.
(3E)-3-(4-Bromobenzylidene)-1,7,7-trimethylbicyclo[2.2.1]-
heptan-2-one (25b). The bicyclic enol phosphate 21 (367 mg,
1.0 mmol) reacted at 25 °C for 2 h according to TP4. The reaction
mixture was cooled to -20 °C, 4-bromobenzaldehyde (204 mg,
1.1 mmol) was added, and the reaction mixture was slowly
warmed to 25 °C. The resulting mixture was then quenched with
a satd aq NH4Cl solution (30 mL), extracted with diethyl ether
(3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After filtration,
the solvent was evaporated in vacuo. Purification by flash chro-
matography (pentane/Et2O = 4:1) furnished the compound 25b
(220 mg, 0.68 mmol, 68%) as a colorless oil: 1H NMR (CDCl3,
300 MHz) δ = 7.50 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H),
7.14 (s, 1H), 3.03 (d, J = 4.0 Hz, 1H), 2.22-2.09 (m, 1H),
1.84-1.73 (m, 1H), 1.59-1.46 (m, 2H), 1.02 (s, 3H), 0.99 (s,
3H), 0.76 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ = 207.9, 142.8,
134.6, 131.9, 131.1, 126.2, 122.8, 57.1, 49.2, 46.7, 30.6, 25.9, 20.6,
18.3, 9.2; IR (ATR) ν~ (cm-1) 3420, 2957, 1720, 1641, 1586, 1491,
1323, 1071, 1064, 1008, 796; MS (70 eV, EI) m/z 320 (100) [Mþ],
318 (98) [Mþ], 303 (37), 275 (22), 249 (19), 236 (38), 196 (21), 128
(37); HRMS (EI) calcd for C17H19OBr 318.0619, found 318.0621
(3E)-3-(Cyclohexylmethylene)-1,7,7-trimethylbicyclo[2.2.1]-
heptan-2-one (25c). The bicyclic enol phosphate 21 (367 mg, 1.0
mmol) was reactedat 25 °C for 2 h according toTP4. The reaction
mixture was cooled to -20 °C, cyclohexylcarbaldehyde (123 mg,
1.1 mmol) was added, and the reaction mixture was slowly
warmed to 25 °C. The resulting mixture was then quenched with
a satd aq NH4Cl solution (30 mL), extracted with diethyl ether
Diethyl 3-(3-Methoxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]hept-
2-en-2-yl Phosphate (23j). The bicyclic enol phosphate 21
(367 mg, 1.0 mmol) reacted at 25 °C for 2 h according to TP4
4374 J. Org. Chem. Vol. 75, No. 13, 2010

Piller et al.
JOCFeatured Article
(3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After filtration,
the solvent was evaporated in vacuo. Purification by flash chro-
matography (pentane/Et2O = 4:1) furnished the compound 25c
(173 mg, 0.70 mmol, 70%) as a colorless oil: 1H NMR (CDCl3,
300 MHz) δ = 6.18 (d, J = 8.9 Hz, 1H), 2.67 (d, J = 4.4 Hz, 1H),
2.22-2.10 (m, 1H), 2.03-1.93 (m, 1H), 1.72-1.56 (m, 6H),
1.42-1.07 (m, 7H), 0.93 (s, 3H), 0.92 (s, 3H), 0.75 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ = 208.0, 141.0, 135.5, 57.7, 47.7, 46.0,
37.99, 32.3, 32.2, 30.09, 26.8, 25.8, 25.5, 20.5, 18.3, 9.2; IR (ATR)
ν~ (cm-1) 2848, 1725, 1662, 1446, 1257, 1109, 1065, 940; MS (70 eV,
EI) m/z 246 (95) [Mþ], 231 (98), 218 (81), 203 (100), 95 (94);
HRMS (EI) calcd for C17H26O 246.1984, found 246.1963.
Acknowledgment. We thank Dr. Arkady Krasovskiy for
preliminary experiments. We thank the Fonds der Che-
mischen Industrie, the Deutsche Forschungsgemeinschaft
(DFG), and the European Research Council (ERC) for
financial support. We also thank Evonik GmbH, BASF
AG, W.C. Heraeus GmbH, and Chemetall GmbH for the
generous gift of chemicals.
Supporting Information Available: NMR spectra of all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 13, 2010 4375