A Method to Accomplish a 1,4-Addition Reaction of Bulky Nucleophiles to Enones and Subsequent Formation of Reactive Enolates

Article abstract of DOI:10.1021/ol010071i

(matrix presented) BF₃-promoted 1,4-addition of bulky aryl groups to α-iodo enones, prepared from the parent enones, afforded β-aryl-α-iodo ketones. Subsequent reaction with EtMgBr furnished the magnesium enolates, which upon reactions with CIP

Full text of DOI:10.1021/ol010071i

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2017-2020
A Method To Accomplish a 1,4-Addition
Reaction of Bulky Nucleophiles to
Enones and Subsequent Formation of
Reactive Enolates
Anthony D. William and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received April 16, 2001
ABSTRACT
BF -promoted 1,4-addition of bulky aryl groups to r-iodo enones, prepared from the parent enones, afforded â-aryl-r-iodo ketones. Subsequent
3
reaction with EtMgBr furnished the magnesium enolates, which upon reactions with ClP(O)(OEt)2 and aldehydes gave enol phosphates and
aldols, respectively. This method was applied successfully to a synthesis of ∆1-trans-tetrahydrocannabinol.
1,4-Addition of organocopper reagents to R,â-unsaturated
carbonyl compounds assisted by BF3‚OEt2 is a standard
method to introduce a bulky group at the â-position of the
carbonyl compounds (for example, 1 + 2 f 3 in Scheme
1).1 Unfortunately, the unreactive nature of the resulting
boron enolates is described by Lipshutz,1c and hence it seems
impossible to enjoy the benefit of the enolate chemistry. To
the best of our knowledge, neither reaction at the R position
nor formation of enol esters (or ethers) for further reactions
has been reported.
In our investigation of the synthesis of tetrahydrocannab-
inol (THC), use of BF3‚OEt2 was indeed indispensable for
the 1,4-addition reaction of the bulky cuprate 2a to enone
1a (R1 ) CMe2(OTES)) (Et2O, -78 °C, 1.5 h), and the
addition product (structure not shown) was isolated in 90%
yield after aqueous workup (Scheme 1). However, the enolate
generated in situ by the above BF3‚OEt2-assisted 1,4-addition
showed no reactivity, as suggested by Lipshutz,1c toward
PhN(Tf)2, Tf2O, or ClP(dO)(OEt)2.2 Since a silyl enol ether
could be metalated to a reactive enolate, we also attempted
reaction of 1a and 2a with TMSCl and HMPA in THF
according to Nakamura.3 However, the reaction did not
furnish the corresponding TMS ether. Addition of n-BuLi
to the boron enolate did not increase the reactivity toward
ClP(dO)(OEt)2.4 In contrast to the bulky cuprate 2a, the
phenyl cuprate 2e, in a control experiment, underwent
reaction with enone 1a smoothly without the assistance of
BF3‚OEt2 (Et2O, -78 °C, 2 h), and the resulting enolate,
upon reaction with ClP(O)(OEt)2 (-78 °C to rt, 1 h), afforded
enol phosphate 4h (R1 ) CMe2(OTES), Ar ) Ph, E ) P(O)-
(OEt)2) in 63% yield. On the other hand, the enolate produced
in situ from 1a and 2e in the presence of BF3‚OEt2 did not
react and therefore did not furnish the phosphate. These
(2) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.
(3) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. Tetra-
hedron Lett. 1986, 27, 4029-4032.
(4) Addition of n-BuLi to the (presumed) copper enolate is reported to
increase the reactivity of the given enolate: Batt, D. G.; Takamura, N.;
Ganem, B. J. Am. Chem. Soc. 1984, 106, 3353-3354.
(1) (a) Tius, M. A.; Kannaangara, G. S. K. J. Org. Chem. 1990, 55,
5711-5714. (b) Rickards, R. W.; Ro¨nneberg, H. J. Org. Chem. 1984, 49,
572-573. (c) Lipshutz, B. H.; Parker, D. A.; Kozlowski, J. A.; Nguyen, S.
L. Tetrahedron Lett. 1984, 25, 5959-5962.
10.1021/ol010071i CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/24/2001

Scheme 1. A Method To Generate the Reactive Enolates
preliminary results prompted us to devise an indirect method.
in Table 1. No difficulty was incurred in the installation of
the bulky aryl groups of 2a-d (entries 1-7), and the yields
of 7a-g were almost the same as that obtained in a control
experiment with the phenyl cuprate 2e and enone 6a (entry
8). A control experiment using 6a and 2a in the absence of
BF3‚OEt2 did not furnish the addition product 7a; instead,
6a was recovered. In addition, the compounds which might
be produced by reaction at the R-position of 6a-c with the
Shown in Scheme 1 is one such method which consists of
1,4-addition of the cuprate 2 to R-iodocycloalkenones 6 and
subsequent transformation of the resulting R-iodo ketones 7
to reactive enolates 8. In the following paragraphs, we present
the fruitful results of this study.
Conversion of enones 1a and 1b to R-iodocyclohexenones
6a and 6b, respectively, with I2 and pyridine in CCl4
proceeded in good yield by the protocol of Johnson,5 which
was originally developed for preparation of 6c. 1,4-Addition
of bulky Ar2Cu(CN)Li2 (2a-d) to R-iodocyclohexenones
6a-c promoted by BF3‚OEt2 was carried out in good yields
to furnish ketones 7a-g (Figure 1) after aqueous workup
and purification by chromatography.6 The result is delineated
1
cuprates 2a-d were not detected by TLC and H NMR
spectroscopy.7
Determination of the relative stereochemistry at the â and
1
γ positions of the 1,4-addition products 7 by H NMR
spectroscopy was ambiguous due to the somewhat small
coupling constants between the protons at these positions
Figure 1.
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Org. Lett., Vol. 3, No. 13, 2001

Scheme 2. Generation of the Reactive Enolate 8a and Its
Table 1. Synthesis of Iodides 7 and Enol Phosphates 4
Reactions with Electrophiles
product 7
product 4
copper
entry
substrate
reagent
no. yield, % no.
yield, %
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6b
6c
6c
6a
2a
2b
2c
2d
2a
2b
2d
2e
7a
7b
7c
7f
7d
7e
7g
7h
72
67
a
74
67
60
68
65
4a
4b
4c
4f
4d
4e
4g
4h
71
70
53
60
63
58
62
63
a Semipurified 7c was converted into 4c.
(4.5-7.5 Hz). However, the stereochemistry of 7b was
determined to be trans by synthesis of ∆1-trans-THC (vide
infra).8 This assignment is consistent with the steric control
approach of the cuprate 2b to enone 1a. We are speculating
that the reaction of other enones and cuprates proceeds in
the same manner to produce the trans stereochemistry as
depicted in structure 7.
The next step, conversion of the R-iodo ketones 7 to the
corresponding enolates 8, was explored first with 7a as a
representative case under the conditions of Borowitz ((EtO)3P
in EtOH or CHCl3; Ph2POMe in CHCl3),9-11 Utimoto
(EtMgBr in Et2O; Et3B in Et2O or PhH),12,13 and Joshi (Zn/
TMSCl/THF).14 Among these protocols, use of EtMgBr was
successful to generate the corresponding enolate 8a from
iodide 7a, and reaction of enolate 8a and (EtO)2P(O)Cl
afforded the enol phosphate 4a in 71% yield (Scheme 2 and
entry 1 of Table 1). This procedure was then applied to
R-iodo ketones 7b-g to furnish the successful results shown
in Table 1.15 The yields were almost identical as those
obtained from a control experiment with 7h (entry 8). Note
(5) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.;
Wovkulich, P. M.; Uskokovi′c, M. R. Tetrahedron Lett. 1992, 33, 917-
918.
(6) Representative procedure for the 1, 4-addition: To an ice-cold
solution of the bis MOM ether of olivetol (2a) (0.72 g, 2.69 mmol) in Et2O
(5 mL) was added n-BuLi (1.57 mL, 2.01 M, 3.14 mmol) in hexane over
10 min. The mixture was stirred at 0 °C for 10 min and then at ambient
temperature for 2 h. In a separate flask was placed CuCN (0.12 g, 1.35
mmol) in Et2O (5 mL), and the flask was cooled to -78 °C. The lithiated
olivetol solution was transferred to the copper suspension over 10 min at
-78 °C. After the addition, the reaction mixture was stirred at 0 °C for 10
min, recooled to -78 °C, and stirred for an additional 30 min. To the
resulting pale yellow solution was slowly added a solution of R-iodocy-
clohexenone 6b (0.25 g, 0.90 mmol) and BF3‚Et2O (0.13 mL, 1.07 mmol)
in Et2O (5 mL) at -78 °C. After 2 h at -78 °C, the solution was poured
into saturated NH4Cl. The product was extracted and purified as usual to
furnish ketone 7d (0.33 g) in 67% yield. Iodides 7a-7h were stable during
purification and handling for the next reaction.
(7) Reactions at the R-position of R-halo ketones and organometallics
have been reported: (a) Negishi, E.; Owczarczyk, Z. R.; Swanson, D. R.
Tetrahedron Lett. 1991, 32, 4453-4456. (b) Johnson, C. R.; Adams, J. P.;
Braun, M. P.; Senanayake, C. B. W. Tetrahedron Lett. 1992, 33, 919-
922. cf. Jabri, N.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1981, 22,
959-962.
that in most cases the enolate generation from 7 was
accomplished in THF rather than Et2O and was better in the
TLC pattern than in Et2O, though THF had been ineffective
in the original report.12
To investigate further the reactivity of the enolates
possessing bulky groups at the â-position, aldol reaction of
1
(8) The characteristic signals for ∆1-trans- and ∆1-cis-THCs in the H
NMR spectra appear at 3.14 and 3.59 ppm, respectively: Taylor, E. C.;
Lenard, K.; Shvo, Y. J. Am. Chem. Soc. 1966, 88, 367-369.
(9) Borowitz, I. J.; Anschel, M.; Firstenberg, S. J. Org. Chem. 1967,
32, 1723-1729.
(10) Borowitz, I. J.; Casper, E. W. R.; Crouch, R. K.; Yee, K. C. J.
Org. Chem. 1972, 37, 3873-3878.
(11) Stork, G.; Isobe, M. J. Am. Chem. Soc. 1975, 97, 4745-4746.
(12) Aoki, Y..; Oshima, K.; Utimoto, K. Chem. Lett. 1995, 463-464.
(13) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991,
64, 403-409.
(14) (a) Joshi, G. C.; Pande, L. M. Synthesis 1975, 450-453. (b)
Hashimoto, S.; Itoh, A.; Kitagawa, Y.; Yamamoto, H.; Nozaki, H. J. Am.
Chem. Soc. 1977, 99, 4192-4194.
(15) Representative procedure for generation of enol phosphates: To
an ice-cold solution of the iodo ketone 7d (0.21 g, 0.38 mmol) in THF (5
mL) was added EtMgBr (0.57 mL, 1 M in THF, 0.57 mmol). After 10 min
of stirring, ClP(O)(OEt)2 (0.14 mL, 0.96 mmol) was added to the resulting
pale yellow solution. The reaction was continued at 0 °C for 2 h and
quenched with saturated NaHCO3. The product was extracted with EtOAc
and purified by chromatography on silica gel (pretreated with Et3N) to afford
the enol phosphate 4d (0.14 g) in 63% yield.
Org. Lett., Vol. 3, No. 13, 2001
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8a with Ph(CH)2CHO and CH2O was examined. The
reactions proceeded as efficiently as those in the simple cases
reported by Utimoto12 to afford 9 and 10, respectively
(Scheme 2). Aldol 10 was then converted to exo enone 11
in good yield by a conventional method.16 These experiments
show that the steric hindrance derived from the bulky aryl
group at the â-position did not diminish the reactivities of
the enolates at the R-position or on the oxygen atom.
Consequently, a variety of manipulations of enone 11 are
possible for synthetic purposes.
Scheme 3. Synthesis of trans-∆1-THCa
Of the phosphates we examined, the synthesis of ∆1-trans-
THC (15)17 was best accomplished with enol phosphate 4b
(Scheme 3). Methylation18 of 4b with MeMgBr in the
presence of Ni(acac)2 afforded 12, and subsequent exposure
to EtSNa in DMF19 resulted in deprotection of the TES group
and one of the MeO groups to furnish 13. Attempted one-
step deprotection of the two MeO groups under more
vigorous conditions was unsuccessful. Cyclization of 13 was
carried out according to the procedure of Evans20 in the
a Reagents and conditions: (a) Ni(acac)2, MeMgCl, THF, 90%;
(b) EtSNa, DMF, 120 °C, 70%; (c) ZnBr2, MgSO4, CH2CI2, 92%;
(d) EtSNa, DMF, 120 °C, 45%.
presence of MgSO4 to afford 1421 in 92% yield without
migration of the double bond. Finally, deprotection of 14
1
with EtSNa afforded 15, and its H NMR spectrum was
identical to the data reported.8,20,22
Acknowledgment. We thank professor Y. Shoyama of
Kyushu University for informing the guidelines to start this
project. This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Government of Japan.
A.W. is grateful for a Sasakawa Scientific Research Grant
from The Japan Science Society.
(16) (a) Posner, G. H.; Gurria, G. M.; Babiak, K. A. J. Org. Chem. 1977,
42, 3173-3180. (b) Yamada, K.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1998, 63, 3666-3672. (c) Kobayashi, Y.; Murugesh, M. G.; Nakano,
M. Tetrahedron Lett. 2001, 42, 1703-1707.
(17) For reviews of cannabinoid synthesis, see: (a) Razdan, R. K. In
Total Synthesis of Natural Products; ApSimon, J., Ed.; John Wiley: New
York, 1981; Vol. 4, pp 185-262. (b) Mechoulam, R.; McCallum, N. K.;
Burstein, S. Chem. ReV. 1976, 76, 75-112.
(18) (a) Hayashi, T.; Fujiwa, T.; Okamoto, Y.; Katsuro, Y.; Kumada,
M. Synthesis 1981, 1001-1003. (b) Sahlberg, C.; Quader, A.; Claesson,
A. Tetrahedron Lett. 1983, 24, 5137-5138.
(19) Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970, 1327-
1328.
(20) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; Von Matt,
P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos,
K. R. J. Am. Chem. Soc. 1999, 121, 7582-7594.
OL010071I
(21) Childers, W. E., Jr.; Pinnick, H. W. J. Org. Chem. 1984, 49, 5276-
5277.
1
(22) New compounds were characterized by H NMR (300 MHz) and
13C (75 MHz) spectroscopy.
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