Grignard-triggered fragmentation of vinylogous acyl triflates: Synthesis of (Z)-6-heneicosen-11-one, the Douglas fir tussock moth sex pheromone

Article abstract of DOI:10.1055/s-2006-939051

Grignard reagents react with vinylogous acyl triflates in toluene via an addition-fragmentation sequence to afford alkynyl ketones. A streamlined synthesis of (Z)-6-heneicosen-11-one, the sex pheromone of the Douglas fir tussock moth, illustrates the utility of this method. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939051

936
LETTER
Grignard-Triggered Fragmentation of Vinylogous Acyl Triflates: Synthesis of
(Z)-6-Heneicosen-11-one, the Douglas Fir Tussock Moth Sex Pheromone
Fragmentation of
V
a
inylogous
v
A
cyl
T
riflate
i
s
d M. Jones, Shin Kamijo, Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Fax +1(850)6448281; E-mail: gdudley@chem.fsu.edu
Received 13 December 2005
O
Abstract: Grignard reagents react with vinylogous acyl triflates in
toluene via an addition–fragmentation sequence to afford alkynyl
8
ketones. A streamlined synthesis of (Z)-6-heneicosen-11-one, the
sex pheromone of the Douglas fir tussock moth, illustrates the
1
utility of this method.
Figure 1 (Z)-6-Heneicosen-11-one (1)
Key words: synthesis, fragmentation, Douglas fir tussock moth
accessible than the corresponding organolithiums. For
example, n-decylmagnesium chloride, which would be
needed for the synthesis of 1 by our method, is commer-
cially available, whereas n-decyllithium is not. We there-
fore set out to optimize the reaction between triflate 2 and
Grignard nucleophiles (Table 1).
We recently disclosed preliminary findings from a carb-
anion-triggered addition–fragmentation methodology that
we are pursuing in our laboratory.1 Unstabilized carbon
nucleophiles add to vinylogous acyl triflates I to generate
[A], a tetrahedral intermediate with a vinylogous nucle-
ofuge. Intermediate [A] then fragments by a Grob-type
pathway2 to afford a tethered keto alkyne (II, Scheme 1).3
Nucleophilic addition (I → A) is faster than fragmentation
(A → II), so overaddition does not occur; R1–M is gener-
ally consumed prior to the formation of ketone II. Viable
carbon nucleophiles for this reaction include organo-
lithium reagents, lithium enolates, and aryl Grignard
reagents.1
Aryl Grignard nucleophiles (e.g., entry 1) trigger frag-
mentation under our original conditions;1 however, alkyl
Grignards were not competent partners (entry 2).
Table 1 Grignard-Triggered Fragmentation of 2a
O
CH3
OTf
O
CH3
R1–M, solvent
R1
–78 °C to 60 °C
2
3
M
R1
O
R1
O
Entry
R1–M
Solventb
Product
3a
Yield (%)
80
R2
R1–M
(– MOTf)
R2
O
R2
R3
0 °C to
60 °C
1
2
3
4
5
6
7
8
PhMgBr
THF
–78 °C
R3
R3
OTf
n
OTf
R3
c
n
n
R3
n-BuMgCl
n-BuMgCl
n-BuMgCl
i-PrMgCl
BnMgBr
THF
3b
–
R3
[A]
I
II
Et2O
3b
24d
Scheme 1 Addition–fragmentation of vinylogous acyl triflates
Toluene
Toluene
Toluene
3b
63–83
c
3c
–
We now report our efforts to apply this method to an effi-
cient synthesis of (Z)-6-heneicosen-11-one (1), the sex
attractant of the Douglas fir tussock moth.4 Insect phero-
mones are of general interest as environmentally benign
pesticide alternatives.5 Such compounds are already part
of the ecosystem; through controlled release of synthetic
pheromones, one can disrupt the mating behavior of the
pest. Pheromone 1 (Figure 1) in particular has attracted
significant synthetic attention.6
3d
73
58
71
n-DecylMgCl Toluene
3e
PhMgBr
Toluene
3a
Ph
Ph
C4H9
C10H21
O
CH3
O
CH3
O
CH3
O
CH3
O
CH3
The impetus for this endeavor derives from the fact that
alkyl Grignard nucleophiles were beyond the scope of our
initial reports. Grignard reagents are sometimes more
3a
3b
3c
3d
3e
a Solution of triflate 2 (1.1 equiv) treated with 1.0 equiv of R1–M (in
Et2O) at –78 °C, warmed to r.t., and then heated at 60 °C for 30 min.
b Note that Et2O is present in each case.
c Product was not obtained in acceptable purity.
SYNLETT 2006, No. 6, pp 0936–0938
0
4.
0
4.
2
0
0
6
d Reaction mixture was heated for 1 h at reflux (ca. 40 °C); fragmen-
tation was incomplete.
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939051; Art ID: S12405ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Fragmentation of Vinylogous Acyl Triflates
937
Toluene is the preferred solvent for the use of alkyl
Grignard reagents in our addition–fragmentation method.
Entries 2–4 are representative of our solvent screening
process; the reaction of triflate 2 in toluene with an
ethereal solution of n-butylmagnesium chloride afforded
good yields of alkynyl ketone 3b (entry 4). Benzyl-
magnesium bromide also reacted smoothly (entry 6), but
branched alkyl Grignard reagents (e.g., isopropylmagne-
sium chloride, entry 5) were significantly less efficient in
this process. The n-decyl nucleophile relevant to the syn-
thesis of 1 provided an acceptable yield of ketone 3e (en-
try 7). We reexamined phenylmagnesium bromide (entry
8), finding a modest and perhaps insignificant decrease in
efficiency as compared to our previous report (entry 1).
Acknowledgment
This research was supported by a grant from the James and Ester
King Biomedical Research Program, Florida Department of Health,
an award from Research Corporation, and by the FSU Department
of Chemistry and Biochemistry. S.K. acknowledges the Japan
Society for the Promotion of Science (JSPS) for the Postdoctoral
Fellowship for Research Abroad (2004). We thank all of these agen-
cies for their support. We thank Dr. Joseph Vaughn for assistance
with the NMR facilities and Dr. Umesh Goli for providing the mass
spectrometry data.
References and Notes
(1) (a) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127,
5028. (b) Kamijo, S.; Dudley, G. B. Org. Lett. 2006, 8, 175;
a full account of this work, which includes a wider range of
nucleophiles, is in preparation.
(2) (a) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl.
1967, 6, 1. (b) Grob, C. A. Angew. Chem., Int. Ed. Engl.
1969, 8, 535. (c) Wharton, P. S.; Hiegel, G. A. J. Org. Chem.
1965, 30, 3254. (d) Weyerstahl, P.; Marschall, H. In
Comprehensive Organic Synthesis, Vol. 6; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, 1041.
We next turned our attention to the synthesis of 1
(Scheme 2). Vinylogous acyl triflate 47 was treated with
n-decylmagnesium bromide to afford keto alkyne 5 in one
step.8 Hydrogenation of alkyne 5 provides the moth
pheromone 1.6b,9 Characterization data for our synthetic
sample10 is in accord with literature reports.6
(3) Analogues of [A] in which the triflate is replaced by a halide
fragment under flash vacuum pyrolysis conditions: Coke, J.
L.; Williams, H. J.; Natarajan, S. J. Org. Chem. 1977, 42,
2380.
(4) Smith, R. G.; Daterman, G. E.; Daves, G. D. Jr. Science
1975, 188, 63.
O
C10H21
O
n-decyl–MgBr
–78 °C to 60 °C
5% Pd/BaSO4
H2, pyridine
1
C5H11
toluene, 2.5 h
80%
MeOH, 97%
(ref. 6b)
4
5
OR
(R = Tf)
Scheme 2 Synthesis of (Z)-6-heneicosen-11-one (1)
(5) (a) Hulme, M.; Gray, T. Environ. Entomol. 1994, 23, 1097.
(b) Welter, S. C.; Pickel, C.; Millar, J.; Cave, F.; Van
Steenwyk, R. A.; Dunley, J. Calif. Agric. 2005, 59, 17.
(6) There are more than thirty previous syntheses of 1. Selected
examples and leading references: (a) Smith, R. G.; Daves,
G. D. Jr.; Daterman, G. E. J. Org. Chem. 1975, 40, 1593.
(b) Kocienski, P. J.; Cernigliaro, G. J. J. Org. Chem. 1976,
41, 2927. (c) Mori, K.; Uchida, M.; Matsui, M. Tetrahedron
1977, 33, 385. (d) Fetizon, M.; Lazare, C. J. Chem. Soc.,
Perkin Trans. 1 1977, 842. (e) Akermark, B.; Ljungqvist, A.
J. Org. Chem. 1978, 43, 4387. (f) Trost, B. M.; Ornstein, P.
L. Tetrahedron Lett. 1981, 22, 3463. (g) Murata, Y.;
Inomata, K.; Kinoshita, H.; Kotake, H. Bull. Chem. Soc. Jpn.
1983, 56, 2539. (h) Reddy, G. B.; Mitra, R. B. Synth.
Commun. 1983, 16, 1723. (i) Pramod, K.; Ramanathan, H.;
Subba Rao, G. S. R. J. Chem. Soc., Perkin Trans. 1 1983, 7.
(j) Sodeoka, M.; Shibasaki, M. J. J. Org. Chem. 1985, 50,
1147. (k) Wenkert, E.; Ferreira, V. F.; Michelotti, E. L.;
Tingoli, M. J. Org. Chem. 1985, 50, 719. (l) Ballini, R. J.
Chem. Soc., Perkin Trans. 1 1991, 1419. (m) Stowell, J. C.;
Polito, M. A. J. Org. Chem. 1992, 57, 4560. (n) White, J.;
Whiteley, C. G. Synthesis 1993, 1141. (o) Hayes, J. F.;
Shipman, M.; Twin, H. J. Org. Chem. 2002, 67, 935.
(7) Acyl triflate 4 (R = Tf) was prepared from 2-pentyl-1,3-
cyclohexanedione12 using triflic anhydride and pyridine by
analogy to our published procedure, see. ref. 1. 1H NMR
(300 MHz, CDCl3): d = 2.75 (t, J = 6.2 Hz, 2 H), 2.47 (t, J =
6.8 Hz, 2 H), 2.32 (t, J = 7.6 Hz, 2 H), 2.07 (app quint, J =
6.5 Hz, 2 H), 1.22–1.42 (m, 6 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 197.3, 161.7, 132.3, 36.9,
31.7, 28.64, 28.65, 28.0, 23.7, 22.2, 20.6, 13.8. HRMS (CI+):
m/z calcd for C12H18O4SF3: 315.0878; found: 315.0893.
(8) Synthesis of Alkynyl Ketone (5)
This anion-triggered C–C bond cleavage calls to mind the
Eschenmoser–Tanabe reaction sequence, one of the clas-
sic fragmentation protocols and a valuable tool for prepar-
ing alkynyl ketones (Scheme 3).11 Vinylogous acyl
triflates provide more direct access to a similar pathway.
For example, a vinylogous methyl ester (4, R = Me) was
advanced to 1 in a four-step process that featured the
Eschenmoser–Tanabe reaction (4 → III → IV → V → 1,
R1 = decyl, R2 = pentyl).6b By enhancing the nucleofugac-
ity of vinylogous ester 4 (Scheme 2, R = Tf vs. Me), one
gains immediate access to the fragmentation product,
streamlining the synthetic sequence.
R1
R1
R1
O
R2
O
R2
O
H2O2, base
TsNHNH2
O
R2
(or other
epoxidation)
acid or base
V
III
IV
Scheme 3 Eschenmoser–Tanabe fragmentation
In summary, we have extended the scope of our anion-
triggered C–C bond cleavage reaction to include alkyl
Grignard nucleophiles, and we applied our findings to the
chemical synthesis of (Z)-6-heneicosen-11-one (1), the
sex attractant of the Douglas fir tussock moth. Within the
context of this study, toluene proved to be a significantly
more effective solvent than THF. We are continuing to
develop this method, and further applications will be
reported in due course.
To a stirred solution of vinylogous acyl triflate 47 (100 mg,
0.32 mmol) in toluene (3 mL) at –78 °C was added n-decyl-
magnesium bromide (0.31 mL, 0.93 M in Et2O, 0.29 mmol).
The reaction mixture was warmed to r.t. over 1 h, heated at
Synlett 2006, No. 6, 936–938 © Thieme Stuttgart · New York

938
D. M. Jones et al.
LETTER
60 °C for 1.5 h, cooled to r.t., quenched with half-sat. NH4Cl
solution (10 mL), and extracted with Et2O. The combined
organic phases were washed with H2O, dried (MgSO4),
concentrated, and purified on silica gel (elution with 1%
EtOAc–hexanes) to afford alkynyl ketone 5 as an oil that
solidified on standing; yield 70 mg (80%). 1H NMR (300
MHz, CDCl3): d = 2.52 (t, J = 7.3 Hz, 2 H), 2.40 (t, J = 7.5
Hz, 2 H), 2.08–2.23 (m, 4 H), 1.74 (app quint, J = 7.0 Hz, 2
H), 1.43–1.64 (m, 4 H), 1.19–1.38 (m, 18 H), 0.83–0.95 (m,
6 H). 13C NMR (75 MHz, CDCl3): d = 210.9, 81.1, 79.1,
43.0, 41.3, 31.9, 31.1, 29.6, 29.5, 29.4, 29.3, 28.8, 23.9, 23.0,
22.6, 22.2, 18.7, 18.2, 14.1, 13.1. HRMS (CI+): m/z calcd for
C21H39O: 307.3001; found: 307.2999.
(10) 1H NMR (500 MHz, CDCl3): d = 5.37–5.41 (m, 2 H), 2.35–
2.41 (m, 4 H), 1.94–2.06 (m, 4 H), 1.63 (app quint, J =7.4
Hz, 2 H), 1.21–1.37 (m, 22 H), 0.85–0.90 (m, 6 H). HRMS
(CI+): m/z calcd for C21H41O: 309.3157; found: 309.3158.
(11) (a) Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta
1967, 50, 708. (b) Felix, D.; Shreiber, J.; Ohloff, G.;
Eschenmoser, A. Helv. Chim. Acta 1971, 54, 2896.
(c) Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett.
1967, 3943. (d) Tanabe, M.; Crowe, D. F.; Dehn, R. L.;
Detre, G. Tetrahedron Lett. 1967, 3739.
(12) (a) Rosenmund, K. W.; Bach, H. Chem. Ber. 1961, 94,
2394. (b) Piers, E.; Grierson, J. R. J. Org. Chem. 1977, 42,
3755.
(9) The Pd/BaSO4 and pyridine must be mixed before adding
alkyne 5 for best results.
Synlett 2006, No. 6, 936–938 © Thieme Stuttgart · New York