The effect of hmpa on the reactivity of epoxides, aziridines, and alkyl halides with organolithium reagents

Article abstract of DOI:10.1021/ja026915q

A kinetic study of the effect of added HMPA cosolvent on the reaction of 2-lithio-1,3-dithiane (1), bis(phenylthio)methyllithium (2), and bis(3,5-bistrifluoromethylphenylthio)methyllithium (3) with methyloxirane (propylene oxide), N-tosyl-2-methylaziridin

Full text of DOI:10.1021/ja026915q

Published on Web 10/17/2002
The Effect of HMPA on the Reactivity of Epoxides, Aziridines, and Alkyl
Halides with Organolithium Reagents
Hans J. Reich,* Aaron W. Sanders, Adam T. Fiedler, and Martin J. Bevan
Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706
Received May 15, 2002
The reaction of epoxides with nucleophiles is a widely used and
1
effective method for the synthesis of alcohols. Related reactions
2
with N-activated aziridines provide access to amines. Simple alkyl,
vinyl-, or alkynyllithium reagents and ketone or ester enolates6
3
4,5a
work poorly, but more nucleophilic carboxylate dianions, meta-
4
loenamines, and stabilized organolithium reagents such as meta-
lated dithianes give generally clean reactions and high yields.7
Because of their relatively low reactivity, it is frequently advanta-
geous to either activate epoxides by addition of a Lewis acid like
boron trifluoride etherate3,8 or activate the nucleophile by addition
of lithium-complexing reagents such as HMPA or DMPU.7 We
report here some observations on the latter reaction of interest to
synthetic chemists.
b,9
Figure 1. Effect of HMPA on rates of reaction of (a) methyloxirane, (b)
N-tosyl-2-methylaziridine, and (c) BuCl, BuI, and/or allyl chloride with 1,
-
1
2
, and 3 in THF at -78 °C (k2 is the second-order rate constant in M
-
1 10
s
).
Scheme 1
as on an epoxide in Scheme 1), the developing negative charge on
oxygen cannot be stabilized by the lithium counterion because a
+
least-motion pathway results in the Li separated from the oxyanion.
1
1a,b
Extensive ab initio calculations on the reaction of LiH, MeLi,
and cuprate species1 with oxirane and alkyl halides have defined
1c
Figure 1 shows the results of a kinetic study of the effect of
HMPA on the rate of reaction of three bis-thio substituted
organolithium reagents, 1, 2, and 3, with methyloxirane, N-tosyl-
the strong requirement for catalysis by lithium and the ion separation
problems of backside S 2 displacements by a CIP. Separated ion
N
pairs (SIPs) should be inherently favored as reactants in such
reactions.12
-methylaziridine, and primary alkyl halides.10
2
The reactivity order of 1:2:3 in THF was 1:29:5 for the epoxide
The key to understanding our data is the dual role played by
HMPA. Strong complexation to lithium weakens the C-Li interac-
tion and increases the fraction of SIP present, with a great
enhancement of nucleophilic reactivity.13 However, the Li -HMPA
complexes are much weaker Lewis acids than THF solvates, so
any lithium assistance to departure of the leaving group is reduced
or eliminated.14
and 1:16:3 for the aziridine. On addition of HMPA, the three lithium
reagents showed wildly different rate effects, as did the electro-
philes. With 1 as the nucleophile, the rate increase on addition of
+
>10 equiv of HMPA was 8000 for the epoxide, 800 000 for the
aziridine, and ca. 140 000 000 for BuCl. For 2, the rate decreased
by a factor of 350 for the epoxide (after an initial small increase),
but increased by 40× for the aziridine and 380× for BuCl. For 3,
the rate decreased by >2500 for the epoxide and 15× for the
aziridine, but stayed constant for the reaction with allyl chloride,
BuBr, and BuI. Thus, the indiscriminate use of cosolvents for
organolithium reactions without mechanistic understanding can be
counterproductive - HMPA can act as a potent catalyst or inhibitor
depending both on the structure of RLi and on the nature of the
electrophile.
We have developed NMR techniques that allow reliable assess-
ment of RLi ion pair status in the presence of HMPA.1 Application
5a
1
5b,c
to the lithium reagents 1, 2, and 3 led to the data in Figure 2.
Qualitatively, 1 is a strong CIP, with little ion pair separation until
equiv of HMPA have been added, and incomplete separation even
2
at 10 equiv of HMPA. Reagent 2 is a weak CIP in THF, with
substantial formation of SIP even before 1 equiv of HMPA was
added. In contrast, 3 is ca. 80% SIP in THF at -78 °C.
Our working hypothesis is that these reactions involve nucleo-
philic attack of the organolithium SIP on the electrophile. The
differences in behavior can be rationalized by competition between
the ease of formation of the SIP (3 . 2 . 1, see Figure 2), the
inherent nucleophilicity of the separated anions (1 . 2 . 3, as
indicated by the relative reactivities at high HMPA equivalents,
How can we rationalize these behaviors? S
strongly contact ion-paired organolithium reagents exhibit the
product-separated ion pair” problem - the cation is unable to
N
2 reactions involving
“
11a
intimately follow the charge. When the monomeric contact ion
pair (CIP) of RLi is the nucleophile in a backside S 2 attack (such
N
*
To whom correspondence should be addressed. E-mail: reich@chem.wisc.edu.
13386
9
J. AM. CHEM. SOC. 2002, 124, 13386-13387
10.1021/ja026915q CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
aziridine and alkyl halides increases until ion separation is complete
+
at ca. 3 equiv of HMPA, consistent with minimal or no Li
assistance.
In summary, the cosolvent HMPA can have either rate-accelerat-
ing or rate-retarding effects on the S 2 reactivity of sulfur-
N
substituted organolithium reagents, depending on the balance
between three factors: the ease of ion pair separation, the inherent
nucleophilicity of the carbanion, and the extent to which lithium
assists the departure of the leaving group (HMPA reduces the Lewis
+
16
acidity of Li ). In THF with 0-2 equiv of HMPA, there is a
complex interplay between all three effects. In THF with excess
HMPA, the relative reactivity is largely determined by the nucleo-
philicity of the bare carbanions.
Figure 2. Effect of HMPA on the fraction of SIP for 1, 2, and 3. The
fraction of SIP for 1 was determined in 3:2 THF/Me2O by line shape
7
simulation of the Li NMR spectra during an HMPA titration at -135
1
5a-c
13
°
C.
The fraction of SIP for 2 and 3 was determined from the
C
chemical shift at -78 °C of the phenyl C-S carbon, which moves from δ
50.3 for the CIP in THF to δ 158.3 for the SIP in THF-HMPA for 2, and
from δ 151.9 for the CIP in ether to δ 162.3 for the SIP in THF-HMPA for
Acknowledgment. We thank the National Science Foundation
for financial support of this work.
1
3
.
Supporting Information Available: Procedures for the kinetic
experiments (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 1), and the extent to which Li+ coordination assists the
departure of the leaving group (large for the epoxide, minor for
the aziridine, none for the halides).16
One indication that SIPs are involved is the inversion of reactivity
between 1 and 2 in THF with all three electrophiles when HMPA
was added. The unexpectedly high relative reactivity of 2 and 3 in
THF results from a more favorable preequilibrium between CIP
and SIP that more than compensates for the much lower inherent
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-
4
nucleophilicity of the carbanion formed from 2 (ca. 10 ) or 3 (ca.
-8
1
0 ) as compared to 1. Some other observations support the notion
that only SIPs are involved: (1) The rate increase on addition of
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several halides with 2. (2) The relative rate of 2-methyloxirane and
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(
7) (a) Seebach, D.; Willert, I.; Beck, A. K.; Gr o¨ bel, B.-T. HelV. Chim. Acta
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4
1
, 1249-1252.
had no detectable effect on the reaction of 2-methyloxirane with 1
or 2 in THF.17 It is the lithium counterion of the SIP which
complexes the epoxide at the transition state; external lithium salts
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(10) The method of initial rates was used. The large dynamic range was covered
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4
are not involved. Rate-enhancing effects of LiClO and other salts
6
in percent conversion (0.05 to 5%), which gives a range of 3.6 × 10 . A
on epoxide opening have been reported for lithium reagents where
ion separation is much more difficult than for 1-3, such as lithium
acetylides5b and enolates.
few points at the fast end (log k > -0.5) are outside of this range; higher
2
2
conversions were unavoidable for these. Values for log k below -7.6
are lower limits (<0.05% reaction in several h). The reactions were
determined to be first order for each nucleophile and electrophile in THF
solution, except for the reaction of BuCl with 1 and 2, where the reaction
was too slow for reliable measurement of rates.
5a
The situation is simplest for 3. The reagent is essentially fully
separated in THF and thus already has maximal nucleophilic
(
11) (a) Harder, S.; Streitwieser, A., Jr.; Petty, J. T.; Schleyer, P. v. R. J. Am.
Chem. Soc. 1995, 117, 3253-59. (b) Harder, S.; van Lenthe, J. H.; van
Eikema Hommes, N. J. R.; Schleyer, P. v. R. J. Am. Chem. Soc. 1994,
+
reactivity. Addition of HMPA reduces the Lewis acidity of Li ,
with a concomitant decrease in the rate of epoxide opening (Figure
1
16, 2508. (c) Mori, S.; Nakamura, E.; Morokuma, K. J. Am. Chem. Soc.
1
1
a). The rate drops much less for the aziridine opening (Figure
b), so lithium assistance is less important and is essentially absent
2000, 122, 7294-7307.
(12) Similar conclusions have been reached for alkylation of enolates: Arnett,
E. M.; Maroldo, S. G.; Schriver, G. W.; Schilling, S. L.; Troughton, E.
B. J. Am. Chem. Soc. 1985, 107, 2091-2099.
for the alkyl halides, which show no change in rate on addition of
HMPA.
(
13) Separated ions can be 3-7 orders of magnitude more reactive than contact
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Soc. 1988, 110, 7778-7785. Krom, J. A.; Streitwieser, A. J. Am. Chem.
Soc. 1992, 114, 8747-8748.
For 1, the opposite effect dominates. The C-Li bond is strong,
and the equilibrium concentration of SIP in THF is exceedingly
small. The addition of HMPA enhances the reaction rate with all
electrophiles, in our hypothesis by increasing the fraction of SIP
present. However, as compared to epoxide opening, the rate increase
is greater by a factor of 100 for the aziridine and 18 000 for the
(14) Reductions in rate of organolithium reactions on addition of HMPA or
1
5b
other coordinating solvents have been occasionally reported: Chang,
C. J.; Kiesel, R. F.; Hogen-Esch, T. E. J. Am. Chem. Soc. 1973, 95, 8446.
Jackman, L. M.; Chen, X. J. Am. Chem. Soc. 1997, 119, 8681-8684.
Sauvetre, R.; Seyden-Penne, J. Tetrahedron Lett. 1976, 3949-3952.
(
(
(
15) (a) Reich, H. J.; Borst, J. P.; Dykstra, R. R.; Green, D. P. J. Am. Chem.
Soc. 1993, 115, 8728-8741. (b) Reich, H. J.; Sikorski, W. H. J. Org.
Chem. 1999, 64, 14-15. (c) Reich, H. J.; Borst, J. P.; Dykstra, R. R.
Tetrahedron 1994, 50, 5869.
16) Complex structure and cosolvents effects traceable to strong interactions
between substrate and lithium cation have also been observed for the
deprotonation of epoxides with amide bases: Ram ´ı rez, A.; Collum, D.
B. J. Am. Chem. Soc. 1999, 121, 11114-11121.
1-chlorobutane alkylation, a reflection of the decreasing importance
of Li catalysis in this series.
Intermediate behavior is shown by 2. At low equivalents of
HMPA, the increased fraction of SIP leads to a small increase in
the rate of epoxide opening. At this stage, the principal form of
+
18
2
the counterion is Li(HMPA) , which presumably still provides
17) LiClO
BuBr in THF.
(18) The Li(HMPA)
4
also had no effect on the rate of alkylation of 1, 2, or 3 with
some electrophilic assistance. Past 2 equiv, conversion to SIP is
complete, and additional HMPA inhibits the reaction as the less
+
of 2 was directly detectable by 7Li and 31P NMR
2
+
spectroscopy at -125 °C at 0.2-1.0 equiv of HMPA.
electrophilic higher HMPA solvates of Li predominate. In contrast
to the reaction with epoxide, the rate of reaction of 2 with the
JA026915Q
J. AM. CHEM. SOC.
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VOL. 124, NO. 45, 2002 13387