Regioselectivity of addition of organolithium reagents to enones: The role of HMPA

Full text of DOI:10.1021/jo981765g

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J . Org. Chem. 1999, 64, 14-15
Regioselectivity of Ad d ition of Or ga n olith iu m
Rea gen ts to En on es: Th e Role of HMP A
Hans J . Reich* and William H. Sikorski
Department of Chemistry, University of Wisconsin,
Madison, Wisconsin 53706
Received August 31, 1998
Hexamethylphosphoramide (HMPA) is a highly polar,
aprotic solvent which coordinates well to lithium, by one
measurement approximately 300 times more strongly than
tetrahydrofuran (THF).1a HMPA is frequently used to
accelerate organolithium reactions. More intriguing are the
instances where it has been used to alter their course, such
as the regiochemistry of additions to R,â-unsaturated
carbonyl compounds (Figure 1).2a Several groups have
directed extensive efforts at elucidating the effects that
changes in solvent, temperature, and steric bulk have on
the regioselectivity of these additions.2,3
F igu r e 1. Demonstration of the effect of HMPA on the kinetic
selectivity of enone addition.2a
Bryson3b and Cohen3a have proposed that the regioselec-
tivity of addition is a function of the ion pair structure of
the lithium reagent, where contact ion pairs (CIP) with an
intact C-Li association give 1,2 addition via a four-centered
transition state, whereas solvent-separated ion pairs (SIP)
give predominantly 1,4 addition. This hypothesis was based
on the observations that the addition of HMPA2e,3 and colder
temperatures2b,3a (conditions which favor SIP formation5)
kinetically favor 1,4 addition.4 This hypothesis could not be
directly tested since no information about the solution
structures of organolithium reagent - HMPA complexes was
available. Here we apply our multinuclear NMR technique1b
to quantify the amount of separated ion in solution and
correlate this with changes in regioisomeric and
diastereomeric product ratios to test this hypothesis.6
To simplify our analysis, we studied stabilized organo-
lithium reagents that are known or expected to be mono-
meric in THF.7 Figure 2 illustrates the effect of HMPA on
the fraction of SIP and on the amount of 1,4 addition to
2-cyclohexenone (2)11 for the anions bis(phenylthio)methyl-
lithium (3),1c tert-butylthio(methylthio)methyllithium (4),
F igu r e 2. Comparison of the amount of SIP in solution for 3-5
(bottom) with the amount of 1,4 addition toward 2 (top) in 3:2 THF/
Et2O at -120 °C.
and 2-methyl-1,3-dithianyllithium (5).1d,8b,c The method by
which we use lithium NMR spectroscopy to determine the
amount of SIP as a function of HMPA concentration has
7
been described.1b The Li NMR spectra were integrated by
full line shape simulation.12 In these SIPs the carbanion and
lithium counterion are separated by at least one layer of
solvent molecules, but remain intimately associated based
on chemical shift1b and reactivity5a effects. The concentration
of free ions for the SIPs of 3, 4, and 5 is not known, but in
low dielectric-constant media such as THF approximately
1% of the ion pairs of 0.1 M lithium fluorenide are
dissociated.5b
(1) (a) Reich, H. J .; Kulicke, K. J . J . Am. Chem. Soc. 1996, 118, 273-
274. (b) Reich, H. J .; Borst, J . P.; Dykstra, R. R.; Green, D. P. J . Am. Chem.
Soc. 1993, 115, 8728-8741. (c) Reich, H. J .; Dykstra, R. R. J . Am. Chem.
Soc. 1993, 115, 7041-7042. (d) Reich, H. J .; Borst, J . P.; Dykstra, R. R.
Tetrahedron, 1994, 50, 5869-5880. (e) Reich, H. J .; Sikorski, W. H.;
Gudmundsson, B. O¨ .; Dykstra, R. R. J . Am. Chem. Soc. 1998, 120, 4035-
4036.
(2) (a) Brown, C. A.; Yamaichi, A. J . Chem. Soc., Chem. Commun. 1979,
100-101. (b) Ogura, K.; Yamashita, M.; Tsuchihashi, G.-i. Tetrahedron Lett.
1978, 1303-1306. (c) Maruoka, K.; Shimada, I.; Imoto, H.; Yamamoto, H.
Synlett 1994, 519-520. (d) Ostrowski, P. C.; Kane, V. V. Tetrahedron Lett.
1977, 3549-3552. (e) Wartski, L.; El Bouz, M.; Seyden-Penne, J .; Dumont,
W.; Krief, A. Tetrahedron Lett. 1979, 1543-1546. (f) Krief, A. Tetrahedron
1980, 36, 2531-2640. (g) Ager, D. J .; East, M. B. J . Org. Chem. 1986, 51,
3983-3992. (h) Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.;
Vonwiller, S. C. J . Org. Chem. 1989, 54, 1960-1968. (i) Hirama, M.
Tetrahedron. Lett. 1981, 22, 1905-1908. (j) Wilson, S. R.; Price, M. F. Synth.
Commun. 1982, 12, 657-63. (k) Still, W. C.; Mitra, A. Tetrahedron Lett.
1978, 2659-2662. (l) Loupy, A.; Lefour, J .-M.; Deschamps, B.; Seyden-
Penne, J . Nouv. J . Chim. 1980, 4, 121-126. (m) Seebach, D.; Locher, R.
Angew. Chem., Int. Ed. Engl. 1979, 18, 957-958.
(3) (a) Cohen, T.; Abraham, W. D.; Myers, M. J . Am. Chem. Soc. 1987,
109, 7923-7924. (b) Dolak, T. M.; Bryson, T. A. Tetrahedron Lett. 1977,
1961-1964.
(4) When the addition is reversible, higher temperatures and the addition
of HMPA can favor 1, 4 addition thermodynamically: see ref 2d.
(5) (a) Hogen-Esch, T. E.; Smid, J . J . Am. Chem. Soc. 1966, 88, 307-
318. Hogen-Esch, T. E. Adv. Phys. Org. Chem. 1977, 15, 153. (b) Hogen-
Esch, T. E.; Smid, J . J . Am. Chem. Soc. 1966, 88, 318-324.
(6) A second hypothesis is that the presence of HMPA may promote a
single electron transfer (SET) reaction, leading to conjugate addition.
However, a mechanistic study using radical probes failed to demonstrate
that this was occurring, at least in the reactions of lithiodithianes: see
Chung, S. K.; Dunn, L. B., J r. J . Org. Chem. 1984, 49, 935-939.
The formation of SIP and production of the 1,4 product
are clearly correlated, but in each case the onset of 1,4-
addition significantly precedes the appearance of the SIP.
For 3, which easily undergoes the CIP to SIP transition on
addition of HMPA, over 50% 1,4 addition is observed even
in the absence of HMPA. For 5, which exhibits the tightest
contact ion of the three, SIPs are not detectable until 1.5
(7) Their monomeric nature in THF solution is supported by a variety
of data, including cryoscopy in THF (for 58b and analogues of 79), the
observation of single C-Li couplings (for 5,8c and analogues of 3,8c 48c and
51d) and the concentration independence of the 1, 2: 1, 4 ratio for several
of the lithium reagents studied (including 33a and (2-pyridyl-
thio)(isopropylthio)methyllithium1e,10).
(8) (a) Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385.
(b) Bauer, W.; Seebach, D. Helv. Chim. Acta 1984, 67, 1972-1988. (c)
Seebach, D.; Gabriel, J .; Ha¨ssig, R. Helv. Chim. Acta 1984, 67, 1083-1099.
(9) Ahlbrecht, H.; Harbach, J .; Hoffmann, R. W.; Ruhland, T. Lieb. Ann.
1995, 211-216. Ruhland, T.; Hoffmann, R. W.; Shade, S.; Boche, G. Chem.
Ber. 1995, 128, 551-556.
(10) Sikorski, W. H. Ph.D. Thesis, University of Wisconsin, Madison,
1997.
(11) The additions were performed at -120 °C. The Supporting Informa-
tion contains a description of a simple device to facilitate mixing and
temperature control during low-temperature additions.
(12) The simulations were performed with the computer program
WINDNMR (Reich, H. J . J . Chem. Educ. Software, 1996, 3D, 2).
10.1021/jo981765g CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/19/1998

Communications
Sch em e 1. Mech a n istic P r op osa l
J . Org. Chem., Vol. 64, No. 1, 1999 15
equiv. of HMPA, where the amount of 1,4 addition has
already reached 90%. Compound 4 shows an intermediate
behavior. The lack of a direct correlation between the CIP/
SIP ratio and the 1,2:1,4 addition suggests that the reactions
are governed by Curtin-Hammett kinetics. If the CIP and
SIP interconvert more readily than they react with an enone,
then the product ratio will not reflect the ground-state CIP/
SIP ratio measured in the NMR experiments (equilibration
is slow on the NMR time scale). Minute amounts of a more
reactive SIP, not detected by NMR, can dominate the
reaction, even though the CIP is unambiguously the domi-
nant ground-state structure.
F igu r e 3. Changes in 1,4 addition and 1,4 diastereomer distribu-
tion as functions of the equivalents of THF in ether (left) and
HMPA with 90 equiv of THF (right) for the reaction of 7 with 8 at
-120 °C in Et2O.
SIPs. Calculations predict that Lewis acid complexation of
the carbonyl group favors 1,2 addition;14 removal of Li+
should lead to more 1,4 addition, as observed. We propose
that the change in diastereomer ratios signals the onset of
an uncatalyzed addition (path C, Scheme 1). A mechanism
in which the lithium cation is inactive (path C) is also
supported by the observation that the same final diastere-
omer ratio was achieved with several equiv. of N,N′-
dimethylpropyleneurea (DMPU),8a as well as when 1 equiv.
of crypt[2.1.1] was added.15 These facts argue against
inhibition of 1,2 addition by a sterically encumbered HMPA-
coordinated catalyst (a behavior analogous to Yamamoto’s
bulky aluminum catalysts2c).
In summary, at least three mechanisms are required to
explain these data. The CIP produces exclusively 1,2 addi-
tion, as hypothesized.3a,16a However, the situation with the
SIP is more complicated. In the presence of HMPA, only 1,4
addition by the SIP is observed for 3, 4, 5, 7 and a number
of other anions.10 We propose that the absence of Li catalysis
is an important factor in achieving clean 1,4 addition. For
well-stabilized anions in the absence of HMPA, when lithium
catalysis is possible and SIPs are energetically accessible
reactive intermediates, mixtures of 1,2 and 1,4 addition are
observed (3, 6, and 7, for example).16
We find that many sulfur-substituted lithium reagents
can be induced to cleanly add either 1,2 or 1,4 to enones.
Figure 3 is a representative example. Lower temperatures
and the addition of HMPA favor 1,4 addition kinetically,4
only occasionally is there an advantage to the use of more
than 2 equiv. of HMPA. Conversely, the use of pure Et2O as
a solvent, particularly at higher temperatures such as 0 °C
(which also improves solubility of the lithium reagent), leads
to clean 1,2 addition (although with strongly contact ions
such as dithianyllithium, exclusive 1,2 addition is achieved
even at -78 °C in THF).
Our first observation inconsistent with a simple CIP-SIP
dichotomy to rationalize the 1,2:1,4 addition was that the
tetrakis(trifluoromethyl) analogue of
3 (bis(3,5-bis(tri-
fluoromethyl)phenylthio)methyllithium, 6), which is almost
fully separated in THF, actually gave a preponderance of
1,2 addition (61%) in 3:2 THF/ether. Addition of 4 equiv. of
HMPA switched this to 88% 1,4 addition. Thus, if we assume
as above that the SIP is more reactive than the CIP, simple
ion separation is not solely responsible for the conjugate
addition. It is very significant that the reaction, which is
34% complete in 30 s at -120 °C in THF-ether, proceeded
to less than 3% in 1 h when 4 equiv. of HMPA were present,
an HMPA-induced reduction in rate by a factor of 1800. We
hypothesize that the rate-retarding and conjugate-addition-
enhancing effects of HMPA for 6 arise from the suppression
of a lithium-catalyzed process. Scheme 1 presents the three
processes we postulate for the reaction: (A) the CIP gives
1,2 addition; (B) reaction of the lithium-complexed enone
with the free carbanion gives a mixture of products, and (C)
the uncatalyzed SIP process gives only 1,4 addition.
These conclusions are supported by the use of diastereo-
meric product ratios as “fingerprints” to track the involve-
ment of the CIP and SIP species. Reactions of phenylthio(3-
methyl)benzyllithium (7), which is similar to 3 in its ion pair
behavior, with 5-trimethylsilyl-2-cyclohexen-1-one13 (8) were
performed in Et2O with incremental amounts of THF added,
followed by incremental amounts of HMPA. The total
amount of 1,4 addition and the diastereomer distribution
within the 1,4 products are shown in Figure 3.
The most significant result from Figure 3 is that the
distribution of 1,4 diastereomers was essentially invariant
as THF was added to ether, despite a change in the total
amount of 1,4 addition from 0 to 65%. This suggests that
the 1,4 products are being produced by the same mechanism
throughout. In the absence of THF, only 1,2 addition is
observed, and we propose that a CIP (A in Scheme 1) is the
only reactive species. The addition of THF to the Et2O
solution increases the solvent strength and stabilizes small
amounts of an SIP species which produces the 1,4 product
principally through path B. Separated ions are not detect-
able in the NMR experiment in the absence of HMPA.
The addition of HMPA causes a dramatic change in the
1,4 diastereomer distribution. Thus HMPA affects the reac-
tion beyond simply causing more of it to proceed through
Ack n ow led gm en t. We thank the National Science
Foundation for financial support of this work, Procter and
Gamble for a fellowship to W.H.S., and Aaron Sanders for
performing the rate experiments with 6.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures, characterization data, and 7Li and 31P spectra of HMPA
titrations of 3-7 (18 pages).
J O981765G
(14) Lefour, J .-M.; Loupy, A. Tetrahedron 1978, 34, 2597-2605.
(15) Lehn, J . M. Pure Appl. Chem. 1980, 52, 2303-2319.
(16) Additional mechanistic complexities must appear with lithiated
nitriles, which give the inverse response to solvent polarity (ether favors 1,
4 addition; THF favors 1, 2 addition). (a) Stork, G.; Maldonado, L. J . Am.
Chem. Soc. 1974, 96, 5272-5274. (b) Hu¨nig, S.; Wehner, G. Chem. Ber. 1980,
113, 302.
(13) Asaoka, M.; Shima, K.; Takei, H. Tetrahedron Lett. 1987, 28, 5669-
5672.