Use of fluoroalkyl as a latent group for internal alkylation: Application to the synthesis of bridged tetrahydrofluorenones

Article abstract of DOI:10.1021/ol800971f

(Chemical Equation Presented) Tetrahydrofluorenones which possess a C9a-fluoroalkyl substituent were efficiently converted to tetrahydrofluorenones which contain a ring bridging C9a-C2. Conditions include a stepwise sequence of conversion to an alkyl brom

Full text of DOI:10.1021/ol800971f

ORGANIC
LETTERS
2008
Vol. 10, No. 14
2983-2985
Use of Fluoroalkyl as a Latent Group for
Internal Alkylation: Application to the
Synthesis of Bridged
Tetrahydrofluorenones
Dann L. Parker, Jr.,* Amy K. Fried, Dongfang Meng, and Mark L. Greenlee
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
dann_parker@merck.com
Received April 28, 2008
ABSTRACT
Tetrahydrofluorenones which possess a C9a-fluoroalkyl substituent were efficiently converted to tetrahydrofluorenones which contain a ring
bridging C9a-C2. Conditions include a stepwise sequence of conversion to an alkyl bromide followed by treatment with base, and a direct
cyclization by treatment with lithium chloride in DMF heated to 150 °C.
Natural product syntheses often feature the use of an
intramolecular alkylation R to a ketone to form a bridging
ring. Internal alkylations are featured in the syntheses of the
skeleton of Scopadulcic Acid B 1,1 and of (-)-prezizanol 2
and related compounds2 (Figure 1). In both of these cases,
a sulfonate, ultimately derived from ozonolysis and subse-
quent reduction of an allyl substituent, was used as the
leaving group.
Generally regarded as unreactive, alkyl fluorides are rarely
Figure 1. Natural product syntheses which feature an intramolecular
used as alkylating agents in organic synthesis. However,
recent reports describe the use of tert-alkyl and allyl fluorides
for intermolecular alkylation mediated by boron trifluoride
or organoaluminums.3 These powerful reactions occur by
abstraction of fluoride to generate a carbocation. An impor-
alkylation.
tant limitation of these methods is that primary alkyl fluorides
were found to be unreactive. However, primary alkyl
fluorides have been successfully coupled with ꢀ-phenylethyl
Grignard reagents in Zr-catalyzed reactions and with vinyl
Grignard reagents in Ni-catalyzed alkylative dimerization
reactions.4 Additionally, magnesium enamides have been
efficiently alkylated with primary alkyl fluorides and cyclo-
hexyl fluoride to provide R-alkylated ketones upon hydroly-
(1) Tagat, J. R.; Puar, M. S.; McCombie, S. W. Tetrahedron Lett. 1996,
37, 8463–8466.
(2) Sakurai, K.; Kitahara, T.; Mori, K. Tetrahedron. 1990, 761–774.
(3) (a) Ooi, T.; Uraguchi, D.; Kagoshima, N.; Maruoka, K. Tetrahedron
Lett. 1997, 32, 5679–5682. (b) Hirano, K.; Fujita, K.; Yormitsu, H.;
Shinokubo, H.; Oshima, K. Tetrahedron Lett. 2004, 45, 2555–2557. (c)
Hirano, K.; Hideki, Y.; Oshima, K. Org. Lett. 2004, 26, 4873–4875.
10.1021/ol800971f CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

sis; however, there were no examples of enamides derived
from enones.5
recently reported an important subclass of the phenolic
tetrahydrofluorenones in which an alkyl bridge connects C9a
and C2 5.9,10 In the course of our efforts to make bridged
analogues in the fused-pyrazolo-class 8, we encountered
difficulties that forced us to improve their synthesis. Initially,
we had successfully prepared compounds represented by 8
from a C9a-alkoxy intermediate 6 which often required
protection as an acetate or benzyl ether. To undergo an
intramolecular alkylation reaction the C9a-alkoxy substituent
was converted to a mesylate or a triflate to obtain the desired
bridged compound. In some cases, this route was complicated
by the formation of a cyclic ether 7 by intramolecular
Michael reaction of carbinol 6.11 Often, but not always, the
resulting ether could be opened and thus remain synthetically
useful. However, this undesired reaction prompted us to
explore a route to 8 that would feature the use of a
tetrahydrofluorenone intermediate 9 substituted with a C9a-
alkyl fluoride, which would serve as the latent bridging ring.
We demonstrated the effectiveness of this strategy by the
synthesis of 13, an important intermediate in the preparation
of C9a-C2 ethyl-bridged pyrazolotetrahydrofluorenones
(Scheme 2).
Halogen exchange of alkyl fluorides is also known.6 Boron
trihalides are particularly effective for this reaction, owing
in part to the strength of the resulting boron-fluoride bond.6c
However, this reaction has seen limited use in synthesis.7
One potential novel application of this reaction would be to
use an alkyl fluoride appended to a synthetic intermediate
so that it can be later activated for intramolecular alkylation.
In this way the fluoride would represent a valuable alternative
to a protected alkoxide with several important advantages:
alkyl fluorides are relatively stable to a variety of conditions,
they are often more easily introduced than their alkoxy
counterparts, and they can be directly activated to a better
leaving group without the need for a deprotection step.
Furthermore this tactic would be particularly useful in cases
where a free hydroxyl group would not be tolerated, e.g.,
due to incompatible functionality.
Scheme 1
Scheme 2
Phenolic tetrahydrofluorenones 3 and fused pyrazolotet-
rahydrofluorenones 4 are potent selective classes of ligands
for the estrogen receptor ꢀ (ERꢀ) (Scheme 1.8 We have
Pyrazoloindanone 10,12 was alkylated with fluoroethyl
bromide to give 11, which was converted to the tetrahydrof-
(4) (a) Terao, J.; Watabe, H.; Kambe, N. J. Am. Chem. Soc. 2005, 127,
3656–3657. (b) Terao, J.; Kambe, N. Bull. Chem. Soc. 2006, 79, 663–672.
(5) Hatakeyama, T.; Ito, S.; Yamane, H.; Nakamura, M.; Nakamura, E.
Tetrahedron. 2007, 63, 8440–8448.
(6) (a) Olah, G. A.; Narang, S. C.; Field, L. D. J. Org. Chem. 1981, 46,
3727–3728. (b) Rozov, L. A.; Lessor, R. A.; Kudzma, L. V.; Ramig, K. J.
Fluorine Chem. 1998, 88, 51–54. (c) Namavari, M.; Satyamurthy, N.; Barrio,
J. R. J. Fluorine Chem. 1995, 72 (1), 89–93.
(9) Wildonger, K. J.; Ratcliffe, R. W.; Mosley, R. T.; Hammond, M. L.;
Birzin, E. T.; Rohrer, S. P. Bioorg. Med. Chem. Lett. 2006, 16, 4462–
4466
.
(10) We have referred to compounds in this paper as substituted
derivatives of 1,2,9,9a-tetrahydro-3H-fluoren-3-ones. The IUPAC name for
the ring system represented by 9 is 8,9,9a,10-tetrahydroindeno[2,1-e]indazol-
7(3H)-one; the ring system of 13 is 3,9,10,11-tetrahydro-8,10a-methanoa-
zuleno[2,1-e]indazol-7(8H)-one; 15 is a 2,8,9,10,11,12-hexahydro-7H-8,11a-
methanocycloocta[3,4]cyclopenta[1,2-e]indazol-7-one; 18a is a gibba-
1,3,4a(10a),4b-tetraen-6-one-methane (1:2); 18c is a 7,8,9,10-tetrahydro-
7,10a-methanocycloocta[a]inden-6(11H)-one.
(7) Theodoridis, G. Tetrahedron Lett. 1998, 39, 9365–9368.
(8) (a) Wilkening, R. R.; Ratcliffe, R. W.; Tynebor, E. C.; Wildonger,
K. J.; Fried, A. K.; Hammond, M. L.; Mosley, R. T.; Fitzgerald, P. M. D.;
Sharma, N.; McKeever; Nilsson, S.; Carlquist, M.; Thorsell, A.; Locco, L.;
Katz, R.; Frisch, K.; Birzin, E. T.; Wilkinson, H. A.; Mitra, S.; Cai, S.;
Hayes, E. C.; Schaeffer, J. M.; Rohrer, S. P Bioorg. Med. Chem. Lett. 2006,
16, 3489–3494. (b) Wilkening, R. R.; Ratcliffe, R. W.; Fried, A. K.; Meng,
D.; Sun, W.; Colwell, L.; Lambert, S.; Greenlee, M.; Nilsson, S.; Thorsell,
A.; Mojena, M.; Tudela, C.; Frisch, K.; Chan, W.; Birzin, E. T.; Rohrer,
S.; Hammond, M. L Bioorg. Med. Chem. Lett. 2006, 16, 3896–3901.
(11) Mori et al. observed a similar result. See ref 2.
(12) Experimental details for the preparation of 10 are included in the
Supporting Information.
2984
Org. Lett., Vol. 10, No. 14, 2008

luorenone 9 by Robinson annulation in 45% yield from 10.
Treatment of 9 with boron tribromide gave 12, which was
treated with potassium hexamethyldisilylamide to give 13
in 88% yield. Compound 13 can then be functionalized to
give biologically interesting analogues such as those repre-
carbonate or DBU (which works for the cyclization of 12)
gave no reaction.
This method was also useful in the preparation of phenolic
bridged tetrahydrofluorenones 5.13 In the case of the con-
struction of a phenolic tetrahydrofluorenone, the lithium
chloride cyclization is a particularly powerful reaction (Table
2). Applying the chemistry from Scheme 2, 4-chloro-5-
methoxyindanone 16 was converted to 9a-fluoroethyl 17a
and 9a-fluoropropyl 17b tetrahydrofluorenones.14 When
treated with lithium chloride in DMF at 150 °C, compound
17a undergoes cyclization and demethylation15 of the anisole
to give compound 18a. Due to the competing demethylation,
the bidged, anisolic tetrahydrofluorenone, 18b, could not be
obtained by this method.16 However, 18b was accessible in
useful yield by treatment of 17a with KHMDS (entry 2).
Propyl-bridged 18c could only be obtained by the original
stepwise manner (entries 3, 4, and 5).
Table 1. Cyclization of Fluoroalkyl
Pyrazolotetrahydrofluorenones
In summary, we have developed a strategy for the
construction of bridged tetrahydrofluorenones that features
the use of a fluoroalkyl substituent as the latent bridging ring.
We believe this strategy to be novel for the construction of
bridged cycloalkenone compounds. Several conditions were
successful to affect the cyclization. While the stepwise
conversion with boron tribromide followed by base was more
general, the lithium chloride cyclization has been a powerful
reaction in our laboratories, particularly when phenolic
analogues are desired. Further discussion of the ERꢀ activity
of these bridged tetrahydrofluorenones will follow in due
course.
entry substrate
conditions
yield
product
1
2
3
4
5
9
9
9
9
14
LiCl, DMF, 150 °C
KHMDS, THF -78 °C to rt 30%
K2CO3, KI, DMAc
DBU, THF 70 °C
(1) BBr3; (2) KHMDS
80-90%
13
13
N.R.a
N.R.a
74%
15
a Isolated starting material.
sented by 8. Additional examples of this novel strategy are
shown in Tables 1 and 2.
Acknowledgment. The authors thank Amanda Makare-
wicz (Department of Preparative Chemistry and Separations,
Merck and Co., Inc.) for a large-scale preparation of 10.
Table 2. Cyclization of Anisolic Fluoroalkyl
Tetrahydrofluorenones
Supporting Information Available: Experimental pro-
cedures and spectral data, including a procedure for the
preparation of 10. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL800971F
(13) For a related report, see: Scott, J. P.; Ashwood, K. M.; Brands,
K. M. J.; Brewer, S. E.; Cowden, C. J.; Dolling, U. H.; Emerson, K. M.;
Gibb, A. D. ; Goodyear, A. ; Oliver, S. F. ; Stewart, G. W. ; Wallace, D. J.
Org. Process Res. DeVel. Published to the Web Nov. 10, 2007; DOI 10.1021/
op700178q.
entry substrate
conditions
yield
product
1
2
3
4
5
17a
17a
17b
17b
17b
LiCl, DMF, 150 °C
67-90%
18a
18b
KHMDS, THF -78 °C to rt 73%a
LiCl, DMF, 150 °C
KHMDS, THF rt
(1)BBr3; (2) KHMDS
N.R.b
N.R.c
67%
(14) 4-Chloro-5-methoxyindanone 16 (Di Stefano, A.; Sozio, P.; Grazia,
L.; Cacciatore, I.; Moscaiatti, B.; Costa, B.; Pinnen, F. Farmaco 2002, 57,
303–313.) was converted by analogy to Scheme 2 to 17a and 17b.
18c
a 93:7 product:s.m. by 1H NMR. b Major product in a complex reaction
mixture is the alkyl chloride. c Isolated starting material.
An alternative to the stepwise cyclization of fluoroethyl
compound 9 to the ethyl-bridged compound 13 was found.
Treatment of 9 with lithium chloride at 150 °C cleanly
afforded 13 (presumably through an intermediate alkyl
chloride) in 80-90% yield (Table 1, entry 1). In a rare
example of alkylation by direct displacement of a primary
alkyl fluoride, KHMDS affected cyclization of 9 in modest
yield (entry 2). However, other bases such as potassium
(15) Bernard, A. M.; Ghiani, M. R.; Piras, P. P.; Rivoldini, A. Synthesis
1989, 287–289.
(16) On the basis of LC-MS and 1H NMR we suspect that the cyclization
proceeds through the C9a-ethyl chloride intermediate, which went to
approximately 5% upon heating at 100 °C overnight. Trace cyclization,
but also trace demethylation, is observed at 120 °C. At temperatures required
to make the cyclization reaction practical (>130 °C), demethylation of both
17a and 18b is competitive. Thus, we were unable to use these conditions
to cleanly obtain 18b.
Org. Lett., Vol. 10, No. 14, 2008
2985