Anionic snieckus-fries rearrangement: Solvent effects and role of mixed agregates

Article abstract of DOI:10.1021/ja804087r

Lithiated aryl carbamates (ArLi) bearing methoxy or fluoro substituents in the meta position are generated from lithium diisopropylamide (LDA) in THF, n-BuOMe, Me₂NEt, dimethoxyethane (DME), N,N,N′,N′- tetramethylethylenediamine (TMEDA), N,N,N′

Full text of DOI:10.1021/ja804087r

Published on Web 09/18/2008
Anionic Snieckus-Fries Rearrangement: Solvent Effects and
Role of Mixed Aggregates
Jason C. Riggs, Kanwal J. Singh, Ma Yun, and David B. Collum*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell UniVersity,
Ithaca, New York 14853-1301
Received May 30, 2008; E-mail: dbc6@cornell.edu
Abstract: Lithiated aryl carbamates (ArLi) bearing methoxy or fluoro substituents in the meta position are
generated from lithium diisopropylamide (LDA) in THF, n-BuOMe, Me
2
NEt, dimethoxyethane (DME),
N,N,N′,N′-tetramethylethylenediamine (TMEDA), N,N,N′,N′-tetramethylcyclohexanediamine (TMCDA), and
6
13
15
hexamethylphosphoramide (HMPA). The aryllithiums are shown with Li, C, and N NMR spectroscopies
to be monomers, ArLi-LDA mixed dimers, and ArLi-LDA mixed trimers, depending on the choice of solvent.
Subsequent Snieckus-Fries rearrangements afford ArOLi-LDA mixed dimers and trimers of the resulting
phenolates. Rate studies of the rearrangement implicate mechanisms based on monomers, mixed dimers,
and mixed trimers.
Introduction
aryl carbamates bearing activating meta substituents (OCH or
3
F) and bulky carbamoyl groups rapidly form a relatively stable
The anionic Snieckus-Fries rearrangement of aryl carbamates
intermediate aryllithium, allowing the rearrangement step to be
(
eq 1a) is a highly effective means of carrying out ortho
8
1
,2
examined as well.
substitutions. Its popularity stems in large part from the
dogged determination of Snieckus and co-workers to optimize
the protocol and expand the scope of the reaction (which
The consistently high yields accompanying eq 1a suggest that
the choice of coordinating solvent is unimportant, but yields
9
3
-6
offer little insight into reactivity. The relative rate constants
prompts us to cast a vote for adding Snieckus to the name).
(
krel) show that the choice of coordinating solvent markedly
influences the rate of acyl transfer. Of course, solvent-dependent
relative reactivities do not offer direct insights into underlying
1
0,11
organolithium structures and reaction mechanisms.
In a previous study we investigated reactivities and mecha-
nisms of the ortholithiation of aryl carbamates, paying only
7
limited attention to the acyl transfer. This paper focuses
Table 1a
5
a
solvent3
(4) (a) The Lewis acid-mediated version was discovered by Fries in 1908
yield
k
rel
5b
A photochemical variant was first described in 1960, and the anionic
5
c
THF
88
84
83
94
87
83
88
5
variant appears to have been first reported by Melvin in 1981.
THF/HMPA
n-BuOMe
DME
TMCDA
TMEDA
Me2NEt
7700
1
Snieckus reported the first anionic Fries rearrangement of an aryl
2
carbamate in 1983.
(
5) (a) Fries, K.; Finck, G. Ber. 1908, 41, 2447. (b) Anderson, J. C.; Reese,
C. B. Proc. Chem. Soc. 1960, 217. (c) Melvin, L. S. Tetrahedron Lett.
90
90
12
2
1
981, 3375.
(
6) Industrial applications:(a) Nguyen, T.; Wicki, M. A.; Snieckus, V. J.
Org. Chem. 2004, 69, 7816. (b) Mhaske, S. B.; Argade, N. P. J. Org.
Chem. 2004, 69, 4563. (c) Harfenist, M.; Joseph, D. M.; Spence, S. C.;
Mcgee, D. P. C.; Reeves, M. D.; White, H. L. J. Med. Chem. 1997,
40, 2466. (d) Piettre, A.; Chevenier, E.; Massardier, C.; Gimbert, Y.;
Greene, A. E. Org. Lett. 2002, 4, 3139. (e) Dankwardt, J. W. J. Org.
Chem. 1998, 63, 3753. (f) Mohri, S.; Stefinovic, M.; Snieckus, V. J.
Org. Chem. 1997, 62, 7072. (g) Lampe, J. W.; Hughes, P. F.; Biggers,
C. K.; Smith, S. H.; Hu, H. J. Org. Chem. 1994, 59, 5147. (h) Ding,
F.; Zhang, Y.; Qu, B.; Li, G.; Farina, V.; Lu, B. Z.; Senanayake, C. H.
Org. Lett. 2008, 10, 1067.
Our interest in the Snieckus-Fries rearrangement was piqued
by its probative value to study organolithium structure-reactivity
relationships. Dimethylcarbamates bearing no meta substituent
favor rapid intramolecular acyl transfer, affording insight into
7
only the slow (rate-limiting) ortholithiation step. By contrast,
(
7) (a) Singh, K. J.; Collum, D. B. J. Am. Chem. Soc. 2006, 128, 13753.
(b) Ma, Y.; Collum, D. B. J. Am. Chem. Soc. 2007, 129, 14818.
(
1) (a) Hartung, C. G.; Snieckus, V. In Modern Arene Chemistry; Astruc,
D., Ed.; Wiley-VCH: Weinheim, 2002; Chapter 10. (b) Snieckus, V.
Chem. ReV. 1990, 90, 879. (c) Taylor, C. M.; Watson, A. J. Curr.
Org. Chem. 2004, 8, 623.
(8) (a) Kauch, M.; Hoppe, D. Can. J. Chem. 2001, 79, 1736. (b) Kauch,
M.; Snieckus, V.; Hoppe, D. J. Org. Chem. 2005, 70, 7149.
(9) Collum, D. B. Acc. Chem. Res. 1992, 25, 448.
(
(
2) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935.
3) LDA ) lithium diisopropylamide (LDA); DME ) 1,2-dimethoxy-
ethane; TMEDA ) N,N,N′N′-tetramethylethylenediamine; TMCDA
(10) (a) Bernstein, M. P.; Collum, D. B. J. Am. Chem. Soc. 1993, 115,
8008. (b) Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 2452.
(c) Zhao, P.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 14411.
(11) Collum, D. B.; McNeil, A. J.; Ramirez, A. Angew. Chem., Int. Ed.
2007, 46, 3002.
)
trans-N,N,N′,N′-tetramethylcyclohexanediamine (optically pure R,R
or S,S enantiomer); and HMPA ) hexamethylphosphoramide.
10.1021/ja804087r CCC: $40.75

2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 13709–13717 9 13709

A R T I C L E S
Riggs et al.
6
15
a,b
exclusively on the acyl transfer. We describe herein studies of
solvent-dependent structures of the intermediate lithiated aryl
carbamates and evidence of monomer-, mixed dimer-, and mixed
Table 1. Li and N NMR Spectroscopic Data
6
1
15
ArLi
solvent
R
X
Li, δ (mult, JLiN)
N, δ(mult)
c
6
6
a
c
THF
i-Pr
F
1.23 (s)
-
-
-
-
-
1
2
trimer-based mechanisms for the rearrangement. The mixed
trimer-based pathway may represent the first documented
example of an organolithium reaction in which the rate-limiting
transition structure is more highly aggregated than the reac-
b
HMPA
HMPA
DME
TMCDA
THF
n-BuOMe Et
DME
TMEDA
2
NEt
i-Pr OMe 0.91 (s)
6e
6f
i-Pr
i-Pr
Et
F
F
0.75 (s)
1.65 (s)
c,b
b
b
6
g
OMe 2.18 (s)
F
OMe 1.85 (d, 5.8)
F
76.3 (q)
75.8 (q)
75.2 (q)
75.3 (q)
75.3 (q)
1
3
7b
i-Pr
1.71 (d, 5.3)
tants.
Results
A series of structural, kinetic, and computational studies are
b
7
7
7
7
8
d
f
g
h
a
b
i-Pr
i-Pr OMe 2.01 (d, 4.9)
Et OMe 1.93 (d,5.2)
1.60 (d, 5.4)
Me
TMEDA
i-Pr OMe 0.78 (d, 5.7) 2.49
73.8 (tt) 75.3 (q)
described below. The choice of substrates was not as arbitrary
as it might seem. Rate studies demand structural homogeneity
(t, 4.7) 2.50 (d, 5.7)
8
9
b
a
Me
2
NEt
Et
OMe 0.81 (d, 6.3) 2.24
d, 6.0)2.80 (t, 4.9)
0.40 (d, 4.8)
74.2 (tt) 74.3 (q)
(
1
1,14
to maximize the clarity of the results.
The wide range of
THF
Me
F
79.1 (q)
75.1 (q)
76.5 (q)
76.3 (q)
solvent-dependent reactivities foreshadowed by eq 1a demanded
tinkering with the carbamoyl group and meta substituent to
optimize the protocol for characterizing the starting aryllithiums
and monitoring the rearrangements. General descriptions of
protocols are followed by specific results organized according
to solvent.
9b
n-BuOMe Et
OMe 0.93 (d, 4.9)
OMe 0.54 (d, 5.3)
9
9
1
c
d
HMPA
HMPA
Et
Me
F
0.66 (d, 4.6)
OMe 1.49 (d, 5.5) 1.55
d, 6.2) 1.89 (t, 5.2)
OMe 1.09 (d, 5.3) 1.12
d, 5.3) 1.58 (t, 4.6)
d
d
0a n-BuOMe Et
74.4 (-) 74.1 (-)
(
d
1
0b HMPA
DME
0d TMEDA
Et
73.2 (-) 74.7 (tt)
(
10c
Me
F
0.95 (d, 4.7) 0.98
(d, 5.1) 1.82 (t, 5.1)
72.9 (q) 74.3 (q)
6
Structural Studies. Lithium diisopropylamide (LDA), [ Li]-
1
1
Me OMe 1.21 (d, 5.0) 1.67 (t, 4.9) 74.9 (q) 75.1 (q)
Et OMe 1.79 (d, 6.2) 1.79 73.8 (tt) 74.3 (tt)
t, 5.1) 1.84 (d, 6.1)
6
15
LDA, and [ Li, N]LDA were prepared as white crystalline
0e
2
Me NEt
1
5,16
(
solids.
Previous investigations of LDA solvated by THF,
n-BuOMe, THF/HMPA, and Me2NEt have revealed dimers
a
Multiplicities are denoted as follows: s, singlet; d, doublet; t, triplet;
3
,17a,d
1
a--d as the sole observable forms.
Bifunctional ligands
6
q, quintet. The chemical shifts are reported relative to 0.30 M LiCl/
1
3
DME and TMEDA afford nonchelated dimers 2a and 2b,
respectively.
MeOH (δ 0.0 ppm) and neat Me NEt (δ 25.7 ppm) at -90 °C.
C
2
3,17b,c
LDA solvated by TMCDA forms exclusively
NMR spectra are referenced to toluene-d8 (δ 137.9 ppm), pentane (δ
3
,17b
14.1 ppm), or THF (δ 67.6 ppm). Chemical shifts are reported in ppm,
monomer 3.
b
and
J
values are reported in Hz. Carbon-13 resonances of the
carbanionic carbons: 6c, δ 158.7 (br s); 6f, δ 150.1 (br d, JFC ) 120.7);
6
g, δ 155.1 (t, JCLi ) 7.7); 7b, δ 150.5 (br d, JFC ) 123); 7d, δ 155.2
c
(
q, JCLi ) 5.7); 7f, δ 154.6 (dq, JFC ) 123, JCLi ) 5.9). 1.0 equiv
6 15 d
[
Li, N]LDA. Obscured by another resonance.
6
6
15
[
Li]LDA or [ Li, N]LDA. Rearrangement in the presence of
excess LDA affords phenolate-based mixed dimers 9a-d and
mixed trimers 10a-e, which were synthesized independently
6
15
by lithiating phenols 5a-c with excess [ Li, N]LDA.
The structural assignments stem from splitting patterns
6
15
13
observed using one-dimensional Li, N, and C NMR
17a
1
6
15
19
6
15
Aryllithiums 6a-g, mixed dimers 7a-h, and mixed trimers
spectroscopies as well as J( Li, N)-resolved and Li, N-
1
8
20
8
a-b were generated from aryl carbamates 4a-e using
HSQC NMR spectroscopies. Spectroscopic data are sum-
marized in Table 1, and spectra are archived in Supporting
Information. Although the structures and affiliated equilibria are
complex, the methods used are well established. In lieu of
detailed descriptions of the assignments for each solvent-
substrate-aggregate combination, a few general statements
should suffice.
(
12) For leading references and discussions of mixed aggregation effects,
see: (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624. (b)
Tchoubar, B.; Loupy, A. Salt Effects in Organic and Organometallic
Chemistry; VCH: New York, 1992; Chapters 4, 5, and 7. (c) Briggs,
T. F.; Winemiller, M. D.; Xiang, B.;.; Collum, D. B. J. Org. Chem.
2
001, 66, 6291. (d) Caubere, P. Chem. ReV. 1993, 93, 2317. (e)
Gossage, R. A.; Jastrzebski, J. T. B. H.; van Koten, G. Angew. Chem.,
Int. Ed 2005, 44, 1448. (f) Seebach, D. In Proceedings of the Robert
A. Welch Foundation Conferences on Chemistry and Biochemistry;
Wiley: New York, 1984; p 93,
(1) Some monomeric aryllithiums could be generated only
6
15
by using 1.0 equiv of [ Li, N]LDA in some cases (6a and 6f),
whereas other monomers are formed even with excess
(
13) The exchange of free and bound TMEDA on a TMEDA-chelated
lithiumamidemonomerappearstoproceedbydimer-basedmechanism:Lucht,
B. L.; Bernstein, M. P.; Remenar, J. F.; Collum, D. B. J. Am. Chem.
Soc. 1996, 118, 10707.
6
15
6
13
[ Li, N]LDA (6b-e and 6g). The anticipated Li- C coupling
13
is seen by C NMR spectroscopy in some cases, but most show
only broad mounds. We have noted, however, that mixtures of
(
(
14) The rate law provides the stoichiometry of the transition structure
relative to that of the reactants: Edwards, J. O.; Greene, E. F.; Ross,
J. J. Chem. Educ. 1968, 45, 381.
such putative aryllithium monomers do not form ArLi-Ar′Li
21
22
heteroaggregates, consistent with the monomer assignment.
15) Kim, Y.-J.; Bernstein, M. P.; Galiano-Roth, A. S.; Romesberg, F. E.;
Fuller, D. J.; Harrison, A. T.; Collum, D. B.; Williard, P. G. J. Org.
Chem. 1991, 56, 4435.
Previous spectroscopic studies strongly support a prevalence
6
13
15
(
(
16) The spins of Li, C, and N are 1, 1/2, and 1/2, respectively.
17) (a) Collum, D. B. Acc. Chem. Res. 1993, 26, 227. (b) Remenar, J. F.;
Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1997, 119, 5567. (c)
Bernstein, M. P.; Romesberg, F. E.; Fuller, D. J.; Harrison, A. T.;
Williard, P. G.; Liu, Q. Y.; Collum, D. B. J. Am. Chem. Soc. 1992,
(18) (a) Lustig, E.; Benson, W. R.; Duy, N. J. Org. Chem. 1967, 32, 851.
(b) Yamagami, C.; Takao, N.; Nishioka, T.; Fujita, T.; Takeuchi, Y.
Org. Magn. Reson. 1984, 22, 439.
(19) Rutherford, J. L.; Collum, D. B. J. Am. Chem. Soc. 1999, 121, 10198.
(20) Xiang, B.; Winemiller, M. D.; Briggs, T. F.; Fuller, D. J.; Collum,
D. B. Magn. Reson. Chem. 2001, 39, 137.
1
14, 5100. (d) Romesberg, F. E.; Gilchrist, J. H.; Harrison, A. T.;
Fuller, D. J.; Collum, D. B. J. Am. Chem. Soc. 1991, 113, 5751.
1
3710 J. AM. CHEM. SOC. 9 VOL. 130, NO. 41, 2008

Anionic Snieckus-Fries Rearrangement
A R T I C L E S
Table 2. Summary of Rate Studies for the Anionic Snieckus-Fries Rearrangement
ArLi
solvent
R
X
temperature °C
LDA Order
solvent order
a
b
7
7
6
6
7
6
a
d
b
d
e
THF
Me
Et
Et
Me
Me
Et
F
-40
15
-65
-78
-60
-25
0, -0.48 ( 0.04
1.08 ( 0.05, 2.4 ( 0.6
c
d
n-BuOMe
HMPA
HMPA
DME
OMe
OMe
F
F
OMe
0, 0.49 ( 0.09
0, -1.10 ( 0.05
e
e
0
0
0
0
0.8 ( 0.1
1.2 ( 0.3
0
0
g
TMCDA
a
b
c
d
e
0
.42 M LDA. 0.098 M LDA. 7.0 M n-BuOMe. 1.3 M n-BuOMe. The order in THF cosolvent is zero.
6
(
3) Mixed trimers (8) display three Li resonances in a 1:1:1
6
15
ratio, manifesting the Li- N coupling consistent with a
Lia-Nb-Lic-Nd-Lie subunit. Each mixed trimer also displays
a triplet of triplets and a quintet in the N NMR spectrum.
The asymmetry confirms the chelation of the carbamate moiety
1
5
as drawn.
6
(
4) Phenolate mixed dimers (9) display characteristic Li
1
5
doublets and N quintets that are consistent with Lia-Nb-Lic
connectivity. The Li resonances of the phenolate mixed dimers
6
are upfield from the aryllithium mixed dimers (7).
6
(
5) Phenolate mixed trimers (10) show three Li resonances
1
5
as two doublets and one triplet in a 1:1:1 ratio. Two
resonances appear as either triplet of triplets or quintets.
The anionic Snieckus-
Fries rearrangement was monitored using an in situ IR spec-
N
Figure 1. Plot of kobsd vs [n-BuOMe] in pentane cosolvent for the
rearrangement of 7d (0.004 M) by LDA (0.075 M) at 15 °C. The curve
7
,27
n
11,28,29
depicts an unweighted least-squares fit to kobsd ) k[n-BuOMe] + k′ (k )
Rate Studies. General Methods.
-
3
-4
(
3.0 ( 0.1) × 10 , n ) -1.10 ( 0.05, k′ ) (4.1 ( 0.1) × 10 ).
3
0
trometer fitted with a 30-bounce, silicon-tipped probe. The
(
24) (a) Crittendon, R. C.; Beck, B. C.; Su, J.; Li, X. W.; Robinson, G. H.
Organometallics 1999, 18, 156. (b) Olmstead, M. M.; Power, P. P. J.
Organomet. Chem. 1999, 408, 1. (c) Girolami, G. S.; Riehl, M. E.;
Suslick, K. S.; Wilson, S. R. Organometallics 1992, 11, 3907. (d)
Bosold, F.; Zulauf, P.; Marsch, M.; Harms, K.; Lohrenz, J.; Boche,
G. Angew. Chem., Int. Ed. 1991, 30, 1455. (e) Hardman, N. J.;
Twamley, B.; Stender, M.; Baldwin, R.; Hino, S.; Schiemenz, B.;
Kauzlarich, S. M.; Power, P. P. J. Organomet. Chem. 2002, 643, 461.
(
f) Wegner, G. L.; Berger, R. J. F.; Schier, A.; Schmidbaur, H. Z.
Naturforsch., B: Chem. Sci. 2000, 55, 995. (g) Schiemenz, B.; Power,
P. P. Angew. Chem., Int. Ed. 1996, 35, 2150. (h) Maetzke, T.; Seebach,
D. HelV. Chim. Acta 1989, 72, 624. (i) Kottke, T.; Sung, K.; Lagow,
R. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 1517.
Figure 2. Plot of kobsd vs [LDA] in 1.3 M n-BuOMe/pentane for the
rearrangement of 7d (0.004 M) at 15 °C. The curve depicts an unweighted
(
25) For representative computational studies of aryllithiums, see: (a)
Krasovsky, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 159. (b) Bachrach, S. M.; Chamberlin, A. C. J. Org. Chem. 2004,
n
-3
least-squares fit to kobsd ) k[LDA] + k′ (k ) (6.3 ( 0.2) × 10 , n )
-4
0
.49 ( 0.09, k′ ) (7.9 ( 0.2) × 10 ). k′ (see b) was set to equal k′ in
6
2
9, 2111. (c) Kwon, O.; Sevin, F.; McKee, M. L. J. Phys. Chem. A
001, 105, 913. (d) Wiberg, K. B.; Sklenak, S.; Bailey, W. F. J. Org.
Figure 3.
2
3-25
2
Chem. 2000, 65, 2014. (e) Kremer, T.; Junge, M.; Schleyer, P. v. R.
Organometallics 1996, 15, 3345. (f) Also, see ref 23b.
of monomers.
Especially large JFC couplings (>100 Hz)
1
3
in the C NMR spectra are similar to those observed in other
orthofluorinated aryllithiums.
2) Mixed dimers (7) available by using excess [ Li, N]LDA
show characteristic Li doublets and N quintets consistent with
the Lia-Nb-Lic connectivity. The asymmetry imparted by
chelation of the carbamate moiety could be observed as two
Li resonances at very low temperature (<-125 °C). C NMR
spectra show quintets due to coupling of the lithiated carbon to
two Li nuclei and, in the case of the meta fluoro species, are
(
26) (a) Menzel, K.; Fisher, E. L.; DiMichele, L.; Frantz, D. E.; Nelson,
7
,23a,b,26
2
T. D.; Kress, M. H. J. Org. Chem. 2006, 71, 2188. (b) JC-F values
6
15
have been correlated with π-bond orders and total electronic charge
(
1
3
6
15
at the C atom: Doddrell, D.; Barfield, M.; Adcock, W.; Aurangzeb,
M.; Jordan, D. J. Chem. Soc., Perkin Trans. 1976, 2, 402.
(27) (a) The homoaggregated phenolates tend to be insoluble, and their
often complex structures in solution are unknown. Structurally
analogous lithium phenolates bearing carbonyl-containing moieties in
the ortho position have been characterized crystallographically: Wang,
Z.; Chai, Z.; Li, Y. J. Organomet. Chem. 2005, 690, 4252. (b) Boyle,
T. J.; Pedrotty, D. M.; Alam, T. M.; Vick, S. C.; Rodriguez, M. A.
Inorg. Chem. 2000, 39, 5133. (c) Clegg, W.; Lamb, E.; Liddle, S. T.;
Snaith, R.; Wheatley, A. E. H. J. Organomet. Chem. 1999, 573, 305.
6
13
6
further split by JFC coupling.
(d) Cetinkaya, B.; Gumrukcu, I.; Lappert, M. F.; Atwood, J. L.; Shakir,
(
(
(
21) Singh, K. J.; Hoepker, A. C.; Collum, D. B. Cornell University, Ithaca,
R. J. Am. Chem. Soc. 1980, 102, 2086. (e) Khanjin, N. A.; Menger,
F. M. J. Org. Chem. 1997, 62, 8923.
NY. Unpublished work.
22) For a discussion and leading references to the use of mixed aggregation
to provide insight into homoaggregation, see ref 47b.
23) (a) Ramirez, A.; Candler, J.; Bashore, C. G.; Wirtz, M. C.; Coe, J. W.;
Collum, D. B. J. Am. Chem. Soc. 2004, 126, 14700. (b) Riggs, J. C.;
Ramirez, A.; Cremeens, M. E.; Bashore, C. G.; Candler, J.; Wirtz,
M. C.; Coe, J. W.; Collum, D. B. J. Am. Chem. Soc. 2008, 130, 3406.
(28) (a) Hsieh, H. L.; Quirk, R. P. Anionic Polymerization: Principles and
Practical Applications; Marcel Dekker: New York, 1996. (b) Wardell,
J. L. In ComprehensiVe Organometallic Chemistry; Wilkinson, G.;
Stone, F. G. A., Abel, E. W., Eds.; Pergamon: New York, 1982; Vol.
1, Chapter 2. (c) Szwarc, M., Ed. Ions and Ion Pairs in Organic
Reactions; Wiley: New York, 1972; Vol. I, II.
(
c) Stratakis, M.; Wang, P. G.; Streitwieser, A. J. Org. Chem. 1996,
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ed.; McGraw-Hill: New York, 1995.
6
¨
W. S.; Gudmundsson, B.O.; Dykstra, R. R.; Phillips, N. H. J. Am.
Chem. Soc. 1998, 120, 7201.
(30) Rein, A. J.; Donahue, S. M.; Pavlosky, M. A. Curr. Opin. Drug DiscoV.
DeV. 2000, 3, 734.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 41, 2008 13711

A R T I C L E S
Riggs et al.
first-order conditions by reestablishing the baseline at the end
of a run, injecting a second aliquot of aryl carbamate, and
confirming that the first and second rate constants are equivalent
(
(10%). The reaction orders are summarized in Table 2.
Computations. Calculations based on density functional
theory (DFT) were performed at the B3LYP/6-31G(d) level of
33
theory using Gaussian 03 and visualized with GaussView 3.09.
Gibbs free energies (∆G°, kcal/mol) include thermal corrections
at 298 K. Calculated transition structures were shown to be
legitimate saddle points by the existence of a single imaginary
frequency. The alkyl groups on the carbamate were modeled
as methyl groups, and LDA was modeled as lithium dimethy-
lamide. THF and n-BuOMe were modeled as dimethylether
(
Me2O). TMCDA was modeled as TMEDA. The results,
comprising 43 calculated reactants and 23 calculated transition
structures, are archived in Supporting Information. Selected
observations are presented in the context of the specific solvents
as described below.
THF. The metalation of 4d and subsequent rearrangement
7
in THF solution were studied previously; the results are
summarized to provide context. Rearrangement of mixed dimer
7
a in THF and excess LDA affords LDA-lithium phenolate
34
mixed dimer 9a. The idealized rate law for the rearrangement
eq 2) is consistent with parallel pathways via transition
(
structures 11 and 12 (eq 4). Computations using Me2NLi/Me2O
suggest that 7a is a monosolvated mixed dimer as drawn, and
they support 11 and 12 implicated by the rate law.
-
d[7a] ⁄ dt )
k′
1
0
2
-1⁄2
[
7a
]
[THF] [LDA] + k′′[7a][THF] [LDA]
(2)
n-BuOMe. Lithiation of 4b with excess LDA/n-BuOMe
affords mixed dimer 7d as the only observable form. Solvation
numbers cannot be ascertained spectroscopically, but DFT
computations (see Supporting Information) suggest that mono-
solvated mixed dimer 7d is favored. Rearrangement of 7d in
n-BuOMe with excess LDA affords LDA-lithium phenolate
mixed dimer 9b and mixed trimer 10a.
carbonyl group provided an excellent handle for following the
loss of the aryllithium (monomer 6 or mixed dimer 7;
-
1
1
670-1690 cm ) and the growth of the aryl carboxamide (9
-1
A plot of kobsd vs n-BuOMe concentration (Figure 1) for the
rearrangement of mixed dimer 7d reveals two limiting behaviors:
or 10; 1590-1610 cm ). Pseudo-first-order conditions were
established by maintaining the aryllithium concentration at 0.004
M. Mixed dimers 7a, 7d, and 7e and monomers 6b, 6d, and 6g
were generated in situ with excess LDA. Solvent concentrations
were high, yet adjustable, using a cosolvent (pentane, hexane,
(
1) an inVerse dependence on n-BuOMe concentration, which
is consistent with a mechanism requiring solvent dissociation,
and (2) a zeroth-order dependence on n-BuOMe concentration,
indicating a nondissociative mechanism. Plots of kobsd vs LDA
concentration (Figures 2 and 3) show a positiVe half-order LDA
dependence with a nonzero intercept at low n-BuOMe concen-
tration (affiliated with the mechanism requiring solvent dis-
sociation) and a zeroth-order LDA dependence at high n-BuOMe
concentration (affiliated with the nondissociative mechanism).
The reaction orders are consistent with the idealized rate law
in eq 4, the mechanisms described generically in eqs 5-7, and
3
1
or toluene). The resulting pseudo-first-order rate constants
kobsd) are independent of the initial concentration of the
(
aryllithium, confirming a first-order dependence. The decays
also follow first-order dependencies, as shown by least-squares
3
2
fits to the nonlinear Noyes equation. Phenolate-based mixed
aggregates 9 and 10 or any unforeseen conversion-dependent
changes were shown to be inconsequential under the pseudo-
(
31) The concentration of the LDA, although expressed in units of molarity,
refers to the concentration of the monomer unit (normality). The
concentrations of solvent are expressed as total concentration of free
(33) (a) Frisch, M. J.; et al. Gaussian 03, revision B.04; Gaussian, Inc.:
Wallingford, CT, 2004. (b) Dennington, R., II; Keith, T.; Millam, J.;
Eppinnett, K.; Hovell, W. L.; Gilliland, R. GaussView, Version 3.09;
Semichem, Inc.: Shawnee Mission, KS, 2003.
(34) We define the idealized rate law as that obtained by rounding the
observed reaction orders to the nearest rational order.
(
uncoordinated) form.
(
32) Briggs, T. F.; Winemiller, M. D.; Collum, D. B.; Parsons, R. L., Jr.;
Davulcu, A. K.; Harris, G. D.; Fortunak, J. D.; Confalone, P. N. J. Am.
Chem. Soc. 2004, 126, 5427.
1
3712 J. AM. CHEM. SOC. 9 VOL. 130, NO. 41, 2008

Anionic Snieckus-Fries Rearrangement
A R T I C L E S
Figure 3. Plot of kobsd vs [LDA] in 7.0 M n-BuOMe/pentane for the
rearrangement of 7d (0.004 M) at 15 °C. The curve depicts an unweighted
Figure 4. Plot of kobsd vs [HMPA] in 10.0 M THF/hexanes cosolvent for
the rearrangement of 6b (0.004 M) by LDA (0.10 M) at -65 °C. The curve
-4
least-squares fit to kobsd ) k[LDA] + k′ (k ) (5.7 ( 0.8) × 10 , k′ ) (7.9
n
-
4
depicts an unweighted least-squares fit to kobsd ) k[HMPA] + k′ (k ) (4.8
(
0.2) × 10 ).
-
3
-3
(
0.2) × 10 , n ) 0.8 ( 0.1, k′ ) (0.5 ( 0.2) × 10 ). Pseudo-first-
order conditions not maintained at 0.05 M HMPA (4); data was omitted
transition structures 13 and 14 (eq 1). Although mixed dimer
d is the observable form, the Snieckus-Fries rearrangement
from the fit.
7
is faster via mixed trimer-based transition structure 13. Calcula-
tions using Me2NLi/Me2O support both 13 and 14 as viable
and suggest a greater preference for 13 (although such a non-
isodesmic comparison should be made with caution if at all).
on HMPA concentration (with a relatively minor nonzero
intercept) consistent with a dominant mechanism requiring
solvation by one additional HMPA. Plots of kobsd vs LDA
concentration and kobsd vs THF concentration reveal zeroth-order
dependencies. The idealized rate law (eq 9) is consistent with
the mechanisms described generically in eq 10 and transition
structure 15. Analogous results are obtained using the fluorinated
aryllithium monomer 6d, albeit at approximately 3-fold slower
rearrangement rates, presumably due to inductive stabilization.
Similar relative reactivities of MeO- and F-substituted aryllithi-
ums were observed for the elimination of lithium halides to form
-1
1⁄2
-
d[7d] ⁄ dt ) k′[7d][n-BuOMe] [LDA]
+
0
0
k ′′ 7d [n-BuOMe] [LDA] (4)
[
]
(
i-Pr NLi)(ArLi)(n-BuOMe) + 1 ⁄ 2(i-Pr NLi)2(n-BuOMe) /
2
2
2
(7d)
(
i-Pr NLi) (ArLi)(n-BuOMe) + (n-BuOMe) (5)
2 2
(
i-Pr
NLi
)
2
(ArLi)(n-BuOMe)f
i-Pr NLi)2(ArLi)(n-BuOMe)]
2
2
3b
benzynes.
+
[
(
(6)
2
(13)
1
0
0
-
d[6b] ⁄ dt ) k′[6b][HMPA] [THF] [LDA]
(9)
(
i-Pr NLi)(ArLi)(n-BuOMe) f
2
q
(7d)
(ArLi)(HMPA)
n
+ HMPA f [(ArLi)(HMPA)n+1]
(6b)
(15)
+
[
(i-Pr NLi)(ArLi)(n-BuOMe)] (7)
2
(
10)
(14)
HMPA. Metalation of 4c and 4e with LDA/HMPA/THF
affords monomers 6c and 6e to the exclusion of mixed
3
5
1
DME. Lithiation of 4e with excess LDA/DME affords mixed
dimer 7f as the sole observable aggregate. Unlike n-BuOMe,
DME can be η - or η -coordinated in either the reactant or the
aggregates even with excess LDA. Unfortunately, JCLi
1
3
6
31
coupling was not observed in the C NMR spectra. Li- P
1
2
3
6
coupling was also absent. Rearrangement of 6b in HMPA/
THF and excess LDA affords LDA-lithium phenolate mixed
dimer 9c and mixed trimer 10b. By contrast, rearrangement of
transition structure. DFT computations indicate that (1) the
1
substitution of n-BuOMe by η -coordinated DME is nearly
2
thermoneutral (eq 12), and (2) the η -coordinated mixed dimer
6
d in HMPA/THF and excess LDA affords only LDA-lithium
1
(
18) is 5.1 kcal/mol favored over the η -coordinated mixed
phenolate mixed dimer 9d.
2
dimer 17 (eq 13). One Li-C bond of η -coordinated mixed
dimer 18 is long (2.88 Å) with an accompanying shortening of
the Li-F contact, however, suggesting cleavage (ring expansion)
to accommodate the second oxygen of DME. Although the
calculations are provocative, the veracity of 18 is undermined
by experimental binding studies (discussed below). The open
dimer motif of 18, however, resurfaces in the context of the
rate studies described below.
A plot of kobsd vs HMPA concentration (Figure 4) for the
rearrangement of monomer 6b reveals a first-order dependence
(
(
35) Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 9198.
36) (a) Reich, H. J.; Kulicke, K. J. J. Am. Chem. Soc. 1995, 117, 6621.
(
b) Reich, H. J.; Green, D. P.; Medina, M. A.; Goldenberg, W. J.;
¨
Gudmundsson, B. O.; Dykstra, R. R.; Philips, N. H. J. Am. Chem.
Soc. 1998, 120, 7201. (c) Reich, H. J.; Sikorski, W. H.; Gudmundsson,
¨
B. O.; Dykstra, R. R. J. Am. Chem. Soc. 1998, 120, 4035. (d) Reich,
H. J.; Holladay, J. A.; Mason, J. D.; Sikorski, W. H. J. Am. Chem.
Soc. 1995, 117, 12137. (e) Reich, H. J.; Borst, J. P.; Dykstra, R. R.;
Green, D. P. J. Am. Chem. Soc. 1993, 115, 8728. (f) Jantzi, K. L.;
Puckett, C. L.; Guzei, I. A.; Reich, H. J. J. Org. Chem. 2005, 70,
Plots of kobsd vs DME concentration and kobsd vs LDA
concentration for the rearrangement of mixed dimer 7e reveal
that the rearrangement is independent of both the DME and
LDA concentrations. The reaction orders are consistent with
7
520.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 41, 2008 13713

A R T I C L E S
Riggs et al.
Figure 5. Theoretical curves describing kobsd vs mole fraction of DME
(XDME) according to eq 17 for mixtures of n-BuOMe and DME. The assumed
values of Keq are as labeled. The relative rate constants for kBuOMe and kDME
correspond to the left and right y-intercepts and arbitrarily assigned as 0.05
and 1.1, respectively.
the idealized rate law in eq 14, the mechanism described
generically in eq 15, and transition structure 19. Notably, the
reaction is much faster (approximately 90 times in eq 1a) than
it is in neat n-BuOMe. The origins of the acceleration are
instructive about the role of chelation in the reactant 7e and
transition structure 19.
The data in Figure 6 shows curvature consistent with slight
preference for solvation by DME compared to n-BuOMe (∆G°
2
) -0.2 kcal/mol). Therefore, either η -coordinated DME is not
1
2
present, or the η and η forms are isoenergetic. For the sake
of further discussion, we depict 7e as containing unchelated
DME as drawn. Although it is unclear why the computations
(
cf. 17 and 18) are so poorly predictive (the Me2NLi model
0
0
-
d[7e] ⁄ dt ) k ′
[
7e
]
[DME] [LDA]
(14)
(15)
could be at fault), the potential importance of the fluoro moiety
to stabilize ring-expanded (open) dimers resurfaces (vide infra).
The nearly equal binding energies of n-BuOMe and DME in
the reactant and 90-fold acceleration of the rearrangement
suggest that DME is chelated in the transition state illustrated
in eq 16. Such “hemilability” of DME-solvated LDA has been
documented on several occasions. Computations show a
significant preference for the chelated form with affiliated ring
expansion, as illustrated in eq 18. (Recall that caution is
warranted here).
‡
(
i-Pr NLi)(ArLi)(DME) f [(i-Pr NLi)(ArLi)(DME)]
2
2
(7e)
(19)
3
8
To understand the binding of DME in mixed dimer 7e we
experimentally measured the relative binding energies of
37
n-BuOMe and DME using a variation of a Job plot as follows.
The rearrangement was carried out in DME/n-BuOMe mixtures
according to Scheme 1. The total concentration of DME and
n-BuOMe is held fixed at 5.0 M. The proportion is expressed
as a mole fraction of DME, X. The observed rate constant is
described as a function of the mole fraction according to eq 17.
Three possible limiting results are illustrated in Figure 5. If
n-BuOMe and DME bind equivalently (Keq ) 1), a plot of kobsd
vs mole fraction of DME will be linear. If chelation causes DME
to be a superior ligand (Keq ) 10), then the rate will rise and
saturate at relatively low DME concentrations. In the unlikely
event that n-BuOMe is superior to DME as a ligand for the
mixed dimer (Keq ) 0.1), then the opposite curvature will be
observed.
2
TMEDA and Me NEt. TMEDA surprisingly affords both
mixed dimer 7g and mixed trimer 8a. We believed that chelation
would disfavor trimers. Is TMEDA failing to chelate? Possibly.
Me2NEt, a nonchelating analog of TMEDA, also affords mixed
dimer and trimer (7h and 8b). Fries rearrangement of the mixed
dimers and trimers in TMEDA and Me2NEt with excess LDA
yield trimers 10d and 10e. Rate studies using mixtures of starting
materials are generally ill advised and were not pursued.
TMCDA. To study the role of a chelating diamine on the
reaction rate and mechanism, we investigated TMCDA as a
strongly coordinating model of TMEDA. Metalation of 4b with
LDA/TMCDA affords only aryllithium monomer 6g even with
excess LDA. This substantial change in structure, when
compared with the results using TMEDA, suggests that TMCDA
chelates and TMEDA does not. Monomer 6g displays a
kobsd ) [kBuOMe + (kDMEK - kBuOMe)XDME] ⁄
eq
[
1 + (K -1)XDME] (17)
eq
Scheme 1
6
13
characteristic Li singlet and C triplet. We were not, however,
1
3
able to observe free and bound TMCDA using C NMR
spectroscopy. DFT calculations using, ironically, TMEDA as a
(
37) See ref 10c and references therein.
1
3714 J. AM. CHEM. SOC. 9 VOL. 130, NO. 41, 2008

Anionic Snieckus-Fries Rearrangement
A R T I C L E S
Scheme 2
Figure 6. Plot of kobsd vs mole fraction of DME (XDME) for the
rearrangement of 7e (0.004 M) by LDA (0.05 M) at -60 °C. The donor
solvent concentration is held constant ([DME] + [n-BuOMe] ) 5.0 M)
using pentane as cosolvent. The curve depicts an unweighted least-squares
-3
fit to kobsd ) (a + bx)/(1 + cx) (a ) (0.0 ( 0.1) × 10 , b ) 1.6 ( 0.5,
c ) 0.5 ( 0.4) such that 1 + c ) Keq (see eq 17). At low DME
concentrations the lithium phenolate precipitated during the reaction; the
value of kobsd (shown as 4) was not included in the fit.
model for TMCDA suggest that the chelate is plausible.
Rearrangement of 6g at -25 °C affords a complex mixture of
phenoxides. The complexity of the product distribution does
not preclude detailed rate studies, however.
Plots of kobsd vs TMCDA concentration and kobsd vs LDA
concentration for the rearrangement of monomer 6g reveal
zeroth-order dependencies. The idealized rate law in eq 19 is
consistent with a single mechanism requiring no net changes
in aggregation or solvation described generically in eq 20 and
3
9
transition structure 22 (eq 2).
0
0
-
d[6g] ⁄ dt ) k ′ [6g][TMCDA] [LDA]
(19)
(20)
‡
(ArLi)(TMCDA)f
[
(ArLi)(TMCDA)
]
(6g)
(22)
relationships. Control over both reactant structures and reaction
rates-two important requisites of transparent mechanistic
studies-demanded taking liberties in the choice of carbamoyl
group and meta substituent. A coherent summary of the results,
however, requires that we also take some linguistic liberties by
largely ignoring the substrate variations and focusing on the
influence of solvent. Scheme 2 summarizes these results. We
do not wish to imply, however, that fluoro and methoxy moieties
are interchangeable; substrate-dependent changes in mechanism
may lurk undetected under the surface. The structures of the
reactants assigned spectroscopically and the putative transition
structures are supported by computations that are largely
archived in Supporting Information.
Discussion
We introduced the work described herein with solvent-
dependent yields and rates of an archetypal Snieckus-Fries
rearrangement shown in eq 1a. Noting that yields do not shed
light on rates and simple relative rate constants do not shed
light on causative organolithium structures and mechanisms, we
embarked on studies of solvent-dependent structure-reactivity
Solution Structures. The solvent-dependent structures of
lithiated aryl carbamates follow fairly conventional patterns. The
most strongly coordinating solvents such as TMCDA and
HMPA promote monomers (6). The most strongly coordinating
ethereal solvent (THF) can afford monomers, but affords mixed
dimers (7) with excess LDA. The less strongly coordinating
n-BuOMe promotes exclusively mixed dimers, whereas the very
(
38) (a) Ramirez, A.; Collum, D. B. J. Am. Chem. Soc. 1999, 121, 11114.
b) Ramirez, A.; Lobkovsky, E.; Collum, D. B. J. Am. Chem. Soc.
(
2
003, 125, 15376. (c) Remenar, J. F.; Collum, D. B. J. Am. Chem.
Soc. 1997, 119, 5573.
(
39) (a) We found that TMCDA prepared from commercially available R,R-
and S,S-1,2-cyclohexanediamines did not afford equivalent rates of
rearrangement. Although the source of the differences was not found,
10a,c,17c,40
weakly coordinating Me2NEt
affords mixtures of mixed
3
9b
dimers and mixed trimers. (Mixed trimers are generally favored
we alleviated the problem by resolving trans-cyclohexanediamine,
17b
by weakly coordinating solvents because of their relatively low
N-methylating and recrystallizing the resulting TMCDA as its HCl
1
7b
7,17a,41,42
salt. We found that the optical purity of trans-1,2-cyclohexanedi-
per-lithium solvation numbers.)
Previous studies, how-
1
3
amine and TMCDA could be evaluated by C NMR spectroscopy
ever, have shown that TMEDA is superior to DME as a
3
9c
by adding 2 equiv of (+)-taddol in toluene-d8. . (b) Larrow, J. F.;
Jacobsen, E. N. Org. Synth. 1998, 10, 96. (c) Seebach, D.; Beck, A. K.;
Heckel, A. Angew. Chem., Int. Ed. 2001, 40, 92.
43
chelating ligand. By the simple paradigm that solvation energy
correlates with aggregation state, therefore, DME appears to
J. AM. CHEM. SOC. 9 VOL. 130, NO. 41, 2008 13715

A R T I C L E S
Riggs et al.
be a stronger ligand than TMEDA given that TMEDA affords
mixed dimers and trimers. Indeed, tacit evidence suggests that
TMEDA is too sterically demanding to chelate mixed dimer 7,
causing TMEDA to function equivalently to the poorly coor-
suggest that the rearrangement proceeds via open dimer 27. This
role of the meta substituent once again provokes thought.
4
4
dinating Me2NEt. On many occasions we have found that the
often cited inverse correlation of solvent donicity (enthalpy of
4
2
solvation) with aggregation number is flawed. In this study,
however, the old paradigm holds true.
Despite its complexity, the structure of the aryllithium was
successfully controlled as monomer 6 (TMCDA and HMPA)
or mixed dimer 7 (THF, n-BuOMe, and DME) as required for
detailed rate studies.
Monomer-Based Reactivity. In the case of HMPA, solvation
by an additional HMPA ligand occurs en route to the transition
state. Two solvents eliciting the highest overall reaction rates
Mixed Trimer-Based Reactivity. Metalations in n-BuOMe in
which mixed dimer 7 is the observable reactant displayed an
11
unusual (possibly unprecedented ) half-order LDA dependence
affiliated with a nonzero intercept. The intercept signifies a
pathway requiring no LDA dissociation from mixed dimer 7,
which implicates a mixed dimer-based pathway as discussed
above. The half-order dependence, in conjunction with an
inverse order n-BuOMe dependence, suggests a rearrangement
mechanism requiring an additional equiValent of LDA monomer.
(
eq 1a) also foster monomer-based pathways; these results
follow conventional wisdom. Previous studies had shown that
THF-solvated mixed dimer 7 can rearrange either directly as
the mixed dimer or via aryllithium monomer following de-
aggregation (see 12). In this instance, the high rates observed
at low LDA concentrations arise from the monomer-based
rearrangement. Overall, as one might expect, the two solvents
that afford observable monomers even in the presence of excess
LDA also promote reaction via monomer-based transition
structures.
Mixed Dimer-Based Reactivity. Mixed dimers are reactive
forms for all of the ethereal solvents (although not exclusively
so). The results in THF present an interesting mechanistic issue.
A first-order THF dependence affiliated with the mixed dimer-
based reaction suggests that a disolvated dimer-based pathway
is operative (eq 4). Computations reveal that one of the
reasonable transition structures has an affiliated expanded ring
resulting from chelation by the meta fluoro group. This
expanded ring is illustrated in transition structure 26. We
expressed some concern (vide supra) that the stability of such
open dimers may be overstated, but we find them interesting.
The stoichiometry must be that of a mixed trimer, [(i-
q 14
Pr2NLi)2(ArLi)(n-BuOMe)]
Of the >100 rate laws measured
11
for LDA-mediated reactions to date, we have not observed
evidence of trimer- or mixed trimer-based reactivity. Moreover,
we are unaware of any documented case of an organolithium
reaction proceeding through a higher aggregation state than that
1
3
observed for the reactants. It is also interesting that simply
changing from THF to n-BuOMe, arguably a fairly subtle
change, causes the rearrangement to change from LDA inhibited
to LDA promoted.
Conclusions
Studies of ortholithiated aryl carbamates show that changes
in solvent afford marked shifts in structure from aryllithium
monomer to LDA-aryllithium mixed dimers and trimers. The
mechanisms of the subsequent Snieckus-Fries rearrangements
underscore a similar structural diversity in the rate-limiting
transition structures. In addition to the insights offered into the
intimate interplay between solvent and substrate to control
solution structure and reaction mechanism, one finds several
surprising observations. The meta substituent on the aryl ring
may play a role in the rearrangement beyond simply stabilizing
the aryllithium that, given the importance of substituted aryl-
1
,45
lithiums in synthesis,
may be of significance. Also, an odd
4
6
variant of hemilability —the penchant for bifunctional ligands
to accelerate organolithium reactions by chelating only in the
A similar effect shows up in rearrangements using DME.
Binding studies show that DME and n-BuOMe are nearly
equivalent ligands toward mixed dimer 7, whereas rate studies
show that the rearrangement is 90 times faster in DME (eq 1a).
We infer, therefore, that DME is not chelated in the reactant
but is chelated in the transition structure (eq 22). Marked rate
accelerations stemming from the hemilability of DME are well
38,47
rate-limiting transition state
—seems to have surfaced. As
a final summarizing note, evidence that an observable mixed
dimer undergoes further aggregation to mixed trimer, once again,
(
44) (a) Bauer, W.; Klusener, P. A. A.; Harder, S.; Kanters, J. A.;
Duisenberg, A. J. M.; Brandsma, L.; Schleyer, P. v. R. Organometallics
1988, 7, 552. (b) K o¨ ster, H.; Thoennes, D.; Weiss, E. J. Organomet.
Chem. 1978, 160, 1. (c) Tecl e´ , B.; Ilsley, W. H.; Oliver, J. P.
Organometallics 1982, 1, 875. (d) Harder, S.; Boersma, J.; Brandsma,
L.; Kanters, J. A. J. Organomet. Chem. 1988, 339, 7. (e) Sekiguchi,
A.; Tanaka, M. J. Am. Chem. Soc. 2003, 125, 12684. (f) Linnert, M.;
Bruhn, C.; Ruffer, T.; Schmidt, H.; Steinborn, D. Organometallics
2004, 23, 3668. (g) Fraenkel, G.; Stier, M. Prepr. Am. Chem. Soc.,
DiV. Pet. Chem. 1985, 30, 586. (h) Ball, S. C.; Cragg-Hine, I.;
Davidson, M. G.; Davies, R. P.; Lopez-Solera, M. I.; Raithby, P. R.;
Reed, D.; Snaith, R.; Vogl, E. M. J. Chem. Soc., Chem. Commun.
1995, 2147. (i) Wehman, E.; Jastrzebski, J. T. B. H.; Ernsting, J.-M.;
Grove, J. M.; van Koten, G. J. Organomet. Chem. 1988, 353, 145. (j)
Becker, J.; Grimme, S.; Fr o¨ hlich, R.; Hoppe, D. Angew. Chem., Int.
Ed. 2007, 46, 1645. (k) Also, see ref 17c.
3
8
documented for LDA-mediated metalations. Computations
(
40) (a) Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1996, 118, 2217.
(
b) Settle, F. A.; Haggerty, M.; Eastham, J. F. J. Am. Chem. Soc. 1964,
86, 2076. (c) Lewis, H. L.; Brown, T. L. J. Am. Chem. Soc. 1970, 92,
664. (d) Brown, T. L.; Gerteis, R. L.; Rafus, D. A.; Ladd, J. A. J. Am.
4
Chem. Soc. 1964, 86, 2135. (e) Quirk, R. P.; Kester, D. E. J.
Organomet. Chem. 1977, 127, 111.
(
(
(
41) Lucht, B. L.; Collum, D. B. Acc. Chem. Res. 1999, 32, 1035.
42) Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 2459.
43) Lucht, B. L.; Bernstein, M. P.; Remenar, J. F.; Collum, D. B. J. Am.
Chem. Soc. 1996, 118, 10707.
1
3716 J. AM. CHEM. SOC. 9 VOL. 130, NO. 41, 2008

Anionic Snieckus-Fries Rearrangement
A R T I C L E S
1
13
suggests that the correlation of aggregation state and reactivity
requires some care. Thus, one is reminded that relationships
among product yields, reaction rates, aggregate structures, and
reaction mechanisms are often quite complex.
NMR Spectroscopic Analyses. Standard H and C NMR
1 6 13
spectra were recorded on a 300 MHz spectrometer. H, Li, C,
and N NMR spectra were recorded on a 400, 500, or 600 MHz
spectrometers. The Li and N resonances are referenced to 0.30
M [ Li]LiCl/MeOH at -90 °C (0.0 ppm) and neat Me
C (25.7 ppm), respectively. The C resonances are referenced to
1
5
6
15
6
2
NEt at -90
Experimental Section
13
°
the CH O resonance of THF at -90 °C (67.6 ppm), the ipso
2
2
Reagents and Solvents. THF, n-BuOMe, DME, Me NEt,
resonance of toluene at 137.9 ppm, and methyl resonance of pentane
at 14.1 ppm.
hexane, toluene, and pentane were distilled from blue or purple
solutions containing sodium benzophenone ketyl. The hydrocarbon
stills contained 1% tetraglyme to dissolve the ketyl. HMPA was
IR Spectroscopic Analyses. Spectra were recorded using an in
situ IR spectrometer fitted with a 30-bounce, silicon-tipped probe.
The spectra were acquired in 16 scans at a gain of 1 and a resolution
of 8 cm- . A representative reaction was carried out as follows:
The IR probe was inserted through a nylon adapter and O-ring seal
into an oven-dried, cylindrical flask fitted with a magnetic stir bar
and a T-joint. The T-joint was capped by a septum for injections
and a nitrogen line. Following evacuation under a full vacuum,
heating, and flushing with nitrogen, the flask was charged with LDA
(25-500 mg) in a solvent/cosolvent solution (9.9 mL) and cooled
in a temperature-controlled bath. After recording a background
spectrum, a carbamate was added to the LDA/solvent/cosolvent
mixture from a dilute stock solution (100 µL, 0.400 M) with stirring.
IR spectra were recorded over the course of the reaction. To account
for mixing and temperature equilibration, spectra recorded in the
first 1.5 min were discarded. All reactions were monitored to >5
half-lives.
dried over CaH
recrystallized as their HCl salts
2
and vacuum distilled. TMEDA and TMCDA were
39,48
and distilled from blue or purple
1
solutions containing sodium benzophenone ketyl. Owing to evidence
that commercially available R,R- and S,S-cyclohexanediamine may
contain impurities that influence reaction rates, we resolved racemic
3
9
trans-1,2-cyclohexanediamine following literature procedures.
6
6
15
LDA, [ Li]LDA, and [ Li, N]LDA were prepared from n-BuLi
and i-Pr NH and recrystallized. Air- and moisture-sensitive
2
1
5
materials were manipulated under argon or nitrogen using standard
glovebox, vacuum line, and syringe techniques. Solutions of n-BuLi
49
and LDA were titrated using a literature method. Aryl carbamates
1
8
4
a-e were prepared by literature procedures.
(
45) (a) Gribble, G. W. In Science of Synthesis; Georg Thieme Verlag:
New York, 2005; Vol. 8.1.14. (b) Clayden, J. Organolithiums:
SelectiVity for Synthesis; Pergamon: New York, 2002. (c) Schlosser,
M. In Organometallics in Synthesis: A Manual, 2nd ed.; Schlosser,
M., Ed.; John Wiley: Chichester, 2002; Chapter 1. (d) Clayden, J. In
The Chemistry of Organolithium Compounds; Rappoport, Z., Marek,
I., Eds.; Wiley: New York, 2004; Vol. 1, p 495.
Acknowledgment. We thank the National Institutes of Health
(GM 39764) and the National Science Foundation for direct support
(
46) For reviews of hemilabile ligands, see: (a) Braunstein, P.; Naud, F.
Angew. Chem., Int. Ed. 2001, 40, 680. (b) Slone, C. S.; Weinberger,
D. A.; Mirkin, C. A. Prog. Inorg. Chem. 1999, 48, 233. (c) Lindner,
E.; Pautz, S.; Haustein, M. Coord. Chem. ReV. 1996, 155, 145. (d)
Bader, A.; Lindner, E. Coord. Chem. ReV. 1991, 108, 27.
of this work and Merck, Pfizer, Boehringer-Ingelheim, R. W.
Johnson, sanofi-aventis, Schering-Plough, and DuPont Pharmaceu-
ticals (Bristol-Myers Squibb) for indirect support. We also thank
Emil Lobkovsky for help with a crystal structure determination.
(
47) (a) Ramirez, A.; Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2006,
1
28, 10326. (b) Liou, L. R.; McNeil, A. J.; Ramirez, A.; Toombes,
Supporting Information Available: NMR, rate, and compu-
tational data; complete reference 33. This material is available
free of charge via the Internet at http://pubs.acs.org.
G. E. S.; Gruver, J. M.; Collum, D. B. J. Am. Chem. Soc. 2008, 130,
859.
48) (a) Rennels, R. A.; Maliakal, A.; Collum, D. B. J. Am. Chem. Soc.
998, 120, 421. (b) Freund, M.; Michaels, H. Ber. 1897, 30, 1374.
49) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879.
4
(
(
1
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J. AM. CHEM. SOC. 9 VOL. 130, NO. 41, 2008 13717