Stereochemistry and mechanism of the bronsted acid catalyzed intramolecular hydrofunctionalization of an unactivated cyclic alkene

Article abstract of DOI:10.1002/chem.201003128

Through employment of deuterium-labeled substrates, the triflic acid catalyzed intramolecular exo addition of the X-H(D) (X=N, O) bond of a sulfonamide, alcohol, or carboxylic acid across the C=C bond of a pendant cyclohexene moiety was found to occur, in

Full text of DOI:10.1002/chem.201003128

DOI: 10.1002/chem.201003128
Stereochemistry and Mechanism of the Brønsted Acid Catalyzed
Intramolecular Hydrofunctionalization of an Unactivated Cyclic Alkene
Rachel E. McKinney Brooner and Ross A. Widenhoefer*[a]
Abstract: Through employment of deu-
terium-labeled substrates, the triflic
acid catalyzed intramolecular exo addi-
hydroamination of N-(2-cyclohex-2’-
enyl-2,2-diphenylethyl)-p-toluene-
A
deuteration of the C2’ position of 1a,
ꢀ
consistent with partial C N bond for-
mation in the highest energy transition
state of catalytic hydroamination. The
results of these studies were consistent
with a mechanism for the intramolecu-
lar hydroamination of 1a involving
concerted, intermolecular proton trans-
fer from an N-protonated sulfonamide
to the alkenyl C3’ position of 1a cou-
pled with intramolecular anti addition
of the pendant sulfonamide nitrogen
atom to the alkenyl C2’ position.
ꢀ
tion of the X H(D) (X=N, O) bond
CHTUNGTRENNUNG
of a sulfonamide, alcohol, or carboxylic
acid across the C=C bond of a pendant
cyclohexene moiety was found to
occur, in each case, with exclusive for-
mation (ꢁ90%) of the anti-addition
product without loss or scrambling of
deuterium as determined by 1H and
2H NMR spectroscopy and mass spec-
trometry analysis. Kinetic analysis of
the triflic-acid-catalyzed intramolecular
[1a] and the activation parameters
DH° =(9.7ꢂ0.5) kcalmolꢀ1 and DS° =
(ꢀ35ꢂ5) calKꢀ1 molꢀ1. An inverse a-
secondary kinetic isotope effect of kD/
kH =(1.15ꢂ0.03) was observed upon
Keywords: amination
acids/bases catalysis
·
Brønsted
· reaction
·
mechanisms · stereoselectivity
Introduction
understanding of the mechanisms of Brønsted acid catalyzed
alkene hydrofunctionalization. Whereas the mechanisms of
Brønsted acid mediated intermolecular alkene hydrofunc-
tionalization have been studied for decades,[7–33] mechanistic
information regarding the corresponding intramolecular
processes is scarce, and none of the available data pertains
to electronically unactivated alkenes. Hosomi et al. have re-
ported that the intramolecular hydroalkoxylation and hydro-
amination of vinylsilanes with alcohols and sulfonamides
occur with around 85% syn stereoselectivity, which was at-
tributed to an intramolecular proton transfer from a proton-
ated nucleophile to the C=C bond of the alkene followed by
stereoselective trapping of the more stable b-silylcarbenium
rotamer.[34] Hartwig and Schlummer proposed a similar
mechanism for the triflic acid (HOTf) catalyzed intramolec-
ular hydroamination of vinylarenes with sulfonamides in-
volving intramolecular proton transfer from the protonated
sulfonamide to the alkene followed by trapping of the re-
sulting benzylic carbenium ion. However, this latter study
included neither stereochemical nor kinetic data.[4]
ꢀ
The catalytic addition of the X H (X=O, N) bond of a ni-
trogen or oxygen nucleophile across the C=C bond of an
electronically unactivated alkene (hydrofunctionalization)
represents an attractive and atom economical approach to
[1]
ꢀ
the formation of C X bonds. Intramolecular processes are
particularly attractive as expedient routes to the synthesis of
oxygen and nitrogen heterocycles. Although much of the
effort in the area of catalytic alkene hydrofunctionalization
has been focused on transition-metal-based processes,
Brønsted acids also catalyze the hydrofunctionalization of
C=C bonds, oftentimes with rates and selectivities compara-
ble to transition-metal-catalyzed methods.[2–5] For this
reason, there is growing concern that a number of metal-
based hydrofunctionalization processes, particularly those
that employ electrophilic metal complexes or metal triflates
in combination with modestly basic nucleophiles, may be
catalyzed by a Brønsted acid generated under reaction con-
ditions.[5,6]
Distinguishing between transition metal and Brønsted
acid catalyzed pathways for intramolecular alkene hydro-
functionalization is complicated by a conspicuous gap in our
Owing to the considerable current interest in the catalytic
intramolecular hydrofunctionalization of electronically un-
AHCTUNGTRENNUNG
activated alkenes,[1] we sought to gain information regarding
the mechanisms of the Brønsted acid catalyzed intramolecu-
lar hydrofunctionalization of unactivated alkenes. Here, we
report the stereochemical analysis of the Brønsted acid cata-
[a] R. E. McKinney Brooner, Prof. R. A. Widenhoefer
Department of Chemistry, Duke University
French Family Science Center, Durham, NC, 27708 (USA)
Fax : (+1)919-660-1605
lyzed intramolecular hydrofunctionalization of
a cyclo-
AHCTUNGTREGhNNNU exene moiety with a sulfonamide, an alcohol, and a carbox-
ylic acid, supported by the kinetic analysis of Brønsted acid
catalyzed intramolecular hydroamination. The results of
these studies, particularly in the case of intramolecular hy-
E-mail: rwidenho@chem.duke.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003128.
6170
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Chem. Eur. J. 2011, 17, 6170 – 6178

FULL PAPER
droamination, support a mechanism involving concerted, in-
termolecular protonation of the alkene coupled with intra-
molecular anti addition of the pendant nucleophile.
eration at either the C7ax (dꢃ1.58 ppm) or C7a (d
ꢃ3.73 ppm) positions (Figure 1c). Taken together, these ob-
ꢀ
servations established the net anti addition of the N H
bond across the pendant C=C bond of [1’,3’-D2]1a without
loss or scrambling of deuterium.
Results
Stereochemistry of the hydroamination: To evaluate the
stereoACHTUNGTRENNUNGselectivity of Brønsted acid catalyzed intramolecular
alkene hydroamination, we targeted the doubly deuterium-
labeled g-alkenyl sulfonamide N-(2-1’,3’-dideuteriocyclohex-
2’-enyl-2,2-diphenylethyl)-p-toluenesulfonamide
([1’,3’-
D2]1a) that has been previously employed to evaluate the
stereoselectivity of gold(I)-catalyzed alkene hydroamina-
tion.[35] Treatment of [1’,3’-D2]1a [(83ꢂ1)% [D2], 17% [D1]
To corroborate the findings outlined in the preceding
paragraph, we evaluated the stereoselectivity of the acid-cat-
alyzed intramolecular deuterioamination of the N-deuterat-
ed isotopomer [N-D1]1a.[39] Treatment of [N-D1]1a (ꢃ90%
1
by MS, ꢃ85% deuterated at C3’ by H NMR spectroscopy]
with a catalytic amount of triflic acid (5 mol%) in toluene
at 858C for 48 h led to 5-exo hydroamination with isolation
of [3a,7eq-D2]2a [(83ꢂ1)% [D2] 16% [D1] by MS) as the ex-
clusive dideuterated isotopomer in 96% yield without loss
of deuterium [Eq. (1)].[36] Single-crystal X-ray analysis of the
protio isotopomer 2a revealed a cis-fused chair cyclohexane
with an equatorial diphenylalkyl substituent and an axial
1
[D1] by H NMR spectroscopy) with a catalytic amount of
deuterated triflic acid (DOTf) (5 mol%) at 858C in toluene
for 48 h led to isolation of [7ax-D1]2a [(90ꢂ1)% [D1] by
MS) as the exclusive deuterated isotopomer in 77% yield
[Eq. (2)]. Integration of the H7eq resonance at d=2.49 ppm
1
1
sulfonamide substituent.[37] High-field H NMR spectroscopy
in the H NMR spectrum of [7ax-D1]2a revealed no signifi-
1
1
(Figure 1a), H-1H COSY, and H-1H NOESY analysis con-
firmed that the solid-state conformation of 2a was preserved
in solution and allowed unambiguous assignment of all ali-
phatic proton resonances.[38] Integration of the H7eq reso-
cant deuteration at this position (Figure 1d), whereas
2H NMR analysis displayed a single resonance at d=
1.58 ppm corresponding to deuteration of the C7ax position
with no detectable deuteration at either the C7eq (d=
2.49 ppm) or the C7a (d=3.73 ppm) positions (Figure 1e).
1
nance at d=2.49 ppm in the H NMR spectrum of [3a,7eq-
D2]2a revealed around 85% deuteration at this position
2
(Figure 1b). More importantly, H NMR analysis of [3a,7eq-
D2]2a displayed an approximate 1:1 ratio of resonances at
d=2.95 (C3a) and 2.49 ppm (C7eq) with no detectable deut-
The absence of deuterium incorporation at the C7a and
the C7eq positions of [7ax-D1]2a in the DOTf-catalyzed cycli-
zation of [N-D1]1a argues against reversible deuteronation
of the C2’ or C3’ carbon atoms of the cyclohexenyl moiety
prior to cyclization. To further probe for reversible protona-
tion/deuteronation of the alkene prior to cyclization, the re-
action of [N-D1]1a (ꢃ90% [D1]) and a catalytic amount of
DOTf (5 mol%) at 608C in toluene was monitored periodi-
2
cally by H NMR spectroscopy and quenched at about 50%
conversion by addition of triethylamine. A similar experi-
1
ment utilizing H NMR analysis of a mixture of [N-D1]1a (
ꢃ90% [D1]) and DOTf (5 mol%) in [D8]toluene was run
1
2
concurrently. H and H NMR analysis of the respective sol-
utions revealed no positional isomerization and no detect-
AHCTUNGTREGaNNNU ble incorporation of deuterium into the C2’ or the C3’ posi-
tions (d=5.68 and 5.58 ppm) of [N-D1]1a. These observa-
tions, together with those outlined above, argue strongly
against a reversible deuteronation of either the cyclohexene
C2’ or C3’ carbon atoms prior to cyclization.
Figure 1. a) Partial 1H NMR spectrum of 2a. b),c) Partial 1H and
2H NMR spectra of [3a,7eq-D2]2a. d),e) Partial 1H and 2H NMR spectra
of [7ax-D1]2a. f) Partial H NMR spectrum of [7a-D1]2a.
2
Chem. Eur. J. 2011, 17, 6170 – 6178
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6171

R. A. Widenhoefer and R. E. McKinney Brooner
Stereoselectivity of the hydroalkoxylation and the hydro-
ACHTUNGTRENNUNGacyloxylation: We extended our stereochemical analysis of
acid-catalyzed alkene hydrofunctionalization to include cat-
alytic hydroalkoxylation and hydroacyloxylation employing
an approach similar to that employed for the intramolecular
hydroamination. In one experiment, treatment of the g-al-
kenyl alcohol [1’,3’-D2]1b (96% [D2] by MS) with a catalytic
amount of triflic acid (5 mol%) led to 5-exo hydroalkoxyla-
tion to form [3a,7eq-D2]2b in 96% yield as the exclusive di-
deuterated isotopomer with no loss or scrambling of deuteri-
1
2
um (95% [D2] by MS) [Eq. (3)]. H and H NMR analysis
of [3a,7eq-D2]2b revealed ꢁ95% deuteration of the C7eq
(d=1.89 ppm) and the C3a (d=2.71 ppm) positions with no
detectable deuteration at the C7ax (d=1.34 ppm) or the C7a
(d=4.12 ppm) positions (Figure 2). Similarly, treatment of
Figure 3. a) Partial 1H NMR spectrum of 2c. b),c) Partial 1H and
2H NMR Spectra of [3a,7eq-D2]2c.
Effect of solvent and acid on the hydrofunctionalization:
The efficiency and stereoselectivity of the Brønsted acid cat-
alyzed intramolecular hydrofunctionalization was evaluated
as a function of the acid and the solvent at 858C (Table 1).
Table 1. Brønsted acid catalyzed Iintramolecular hydrofunctionalization
of substrates [D2]1 at 858C for 48 h as a function of the solvent and the
acid (5 mol%).
Entry Substrate
Solvent Acid Product[a,b]
Conversion [%][b]
1
2
3
4
N
ꢁ95
ꢁ95
Figure 2. a) Partial 1H NMR spectrum of 2b. b),c) Partial 1H and
2H NMR spectra of [3a,7eq-D2]2b. d),e) 2H NMR spectra of [7ax-D1]2a.
f) Partial H NMR spectrum of [7a-D1]2a.
54
5
6
U
36
43
2
7
8
9
10
11
12
U
HCl [3a,7eq-D2]2a
HCl [3a,7eq-D2]2b
HCl [3a,7eq-D2]2c
11
b-alkenyl carboxylic acid [1’,3’-D2]1c (>99% [D2] by MS)
with a catalytic amount of triflic acid (5 mol%) led to 5-exo
hydroacyloxylation to form [3a,7eq-D2]2c as the exclusive di-
deuterated isotopomer (>98% [D2] by MS) in quantitative
ꢄ5
ꢄ5
12
22
ꢄ5
1
2
yield [Eq. (4)]. H and H NMR analysis of [3a,7eq-D2]2c re-
vealed ꢁ95% deuteration of the C7eq (d=2.16 ppm) and
the C3a (d=3.07 ppm) positions with no detectable deutera-
tion at the C7ax (d=1.55 ppm) or the C7a (d=4.61 ppm) po-
sitions (Figure 3). In both cases, these results established the
[a] Stereoselectivity was ꢁ90% in all cases. [b] Conversion and stereo-
1
selectivity were determined by H NMR of the purified reaction mixture.
Treatment of substrates [1’,3’-D2]1 with a catalytic amount
of triflic acid (5 mol%) in diglyme at 858C for 48 h led, in
each case, to complete consumption of starting material to
form the 5-exo hydrofunctionalization products [3a,7eq-D2]2
as the exclusive dideuterated isotopomers (Table 1, en-
tries 1–3). In comparison, reaction of substrates [1’,3’-D2]1
with triflic acid in acetonitrile effected a significant decrease
in reaction rate but led, in each case, to formation of the 5-
exo hydrofunctionalization products [3a,7eq-D2]2 as the ex-
clusive isotopomers (Table 1, entries 4–6). Attempts to cy-
clize substrates [1’,3’-D2]1 with weaker acids such as HCl or
trifluoroacetic acid (TFA) in toluene at 858C for 48 h gave
low conversions (Table 1, entries 7–12).
ꢀ
net anti addition of the O H bond across the C=C bond of
the cyclohexene moiety.
Kinetics of the hydroamination: We sought to gain addition-
al information regarding the mechanism of Brønsted acid
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Intramolecular Hydrofunctionalization of an Unactivated Cyclic Alkene
FULL PAPER
catalyzed hydroamination through kinetic analysis of the
triflic acid catalyzed conversion of 1a to 2a. To this end, re-
action of 1a (0.50m) with a catalytic amount of HOTf
(25 mm) in toluene at 628C was analyzed periodically by
liquid chromatography. A plot of ln[1a] versus time was
linear to about three half lives with an observed rate con-
stant of kobs =(4.2ꢂ0.1)ꢁ10ꢀ3 sꢀ1, which established the
first-order dependence of the rate on [1a] (Figure 4; Table 2,
Figure 5. Plot of kobs versus the concentration of triflic acid for the con-
version of 1a ([1a]0 =0.5m) to 2a in toluene at 628C.
Figure 4. First-order plots for the conversion of 1a ([1a]0 =0.50m) to 2a,
*
catalyzed by triflic acid ([HOTf]=5.0 (&), 12.6 ( ), and 25.2 mm (ꢁ)) in
toluene at 628C.
Figure 6. Eyring plot for the conversion of 1a ([1a]0 =0.5m) to 2a, cata-
lyzed by HOTf (25 mm) in toluene over the temperature range 39–728C.
Table 2. Observed rate constants for the conversion of 1a ([1a]0 =0.5m)
to 2a catalyzed by HOTf in toluene as a function of temperature and
HOTf concentration.
Entry
Concentration of HOTf [mm]
T [8C]
kobs [ꢁ103 msꢀ1
]
tion parameters: DH° =(9.7ꢂ0.5) kcalmolꢀ1 and DS° =
(ꢀ34ꢂ5) calKꢀ1 molꢀ1 (Figure 6).
1
2
3
4
5
6
7
25
62.5
62.5
62.5
38.5
45.5
53.0
72.0
4.2ꢂ0.1
12.6
5.0
25
25
25
1.54ꢂ0.07
0.511ꢂ0.007
1.15ꢂ0.04
1.02ꢂ0.03
2.10ꢂ0.08
2.29ꢂ0.07
Hartwig and Schlummer have shown that N-alkyl-p-
toluenesulfonamides are quantitatively protonated by triflic
acid,[4] consistent with the significantly greater acidity of
HOTf (pKa ꢃꢀ15) relative to a protonated sulfonamide
(pKa ꢃꢀ5);[40–42] it is also known that sulfonamides are pro-
tonated at nitrogen rather than at oxygen.[43] Therefore, the
active catalytic species in the conversion of 1a to 2a is most
likely an N-protonated sulfonamide. Laughlin[41] and Olavi
et al.[42] have shown that the conjugate acids of N-alkyl sul-
fonamides are more acidic than the conjugate acids of N,N-
dialkyl sulfonamides by ꢃ0.5 pKa (H0) units. However, if
1a·HOTf were more acidic than 2a·HOTf, deviation from
first-order behavior in the conversion of 1a to 2a would be
observed due to the changing composition of the acidic spe-
cies with increasing conversion. Because no significant devi-
ation from linearity was observed in any of the pseudo first-
order plots for the conversion of 1a to 2a (Figure 4), it ap-
pears that the acidity and/or the reactivity of 1a·HOTf and
2a·HOTf are not significantly different. For these reasons,
25
entry 1). To determine the dependence of the rate on the
concentration of the triflic acid, observed rate constants for
the conversion of 1a to 2a were determined at [HOTf]=5.0
and 12.6 mm (Figure 4; Table 2, entries 2 and 3). A plot of
kobs versus [HOTf] was linear (Figure 5), which established
the first-order dependence of the rate on [HOTf] and the
second-order rate law: rate=k2[1a]ACTHUNTRGNEU[GN HOTf] where k2 =
(1.37ꢂ0.04)ꢁ10ꢀ1 mꢀ1 sꢀ1 (DG°336K =(21.2ꢂ0.1) kcalmolꢀ1).
To determine the activation parameters for the triflic-acid-
catalyzed conversion of 1a to 2a, second-order rate con-
stants for the conversion of 1a to 2a were determined as a
function of the temperature from 39 to 728C (Table 2, en-
tries 4–7). An Eyring plot of these data provided the activa-
the rate law for the conversion of 1a to 2a of k2[1a]
ACHTUNGTRENNUNG
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R. A. Widenhoefer and R. E. McKinney Brooner
is more appropriately described as rate=k2[1a]
[R2NTs·HOTf] (R2NTs=1a and 2a).
77% yield without detectable loss or scrambling of deuteri-
um as determined by MS and 2H NMR analysis [Eq. (5);
Figure 1 f].
a-Secondary kinetic isotope effect: a-Secondary kinetic iso-
tope effects (KIEs) have been utilized to probe for transi-
tion-state rehybridization in the elucidation of a range of or-
ganic reaction mechanisms.[44] As was outlined by Steitwies-
er et al.,[45] a-secondary KIEs are typically attributed to
ꢀ
changes in the stretching and bending frequencies of a C H
bond undergoing ground-state to transition-state rehybridi-
zation.[46] Because C H stretching and in-plane bending fre-
ꢀ
quencies differ little between sp3 and sp2 centers, a-KIEs
arise primarily from the significantly higher out-of-plane
Discussion
3
ꢀ1
ꢀ
bending frequency of an sp C H bond (ꢃ1340 cm ) rela-
ꢀ1
tive to an sp2 C H bond (ꢃ800 cm ), which produces a
Mechanisms of intermolecular electrophilic alkene hydro-
functionalization: Extensive kinetic analyses of the Brønsted
acid catalyzed hydration and intermolecular hydroalkoxyla-
tion of conjugated and nonconjugated alkenes reveal that
with few exceptions, these transformations occur through ir-
reversible, turnover-limiting protonation of the C=C bond
followed by nucleophilic trapping of a solvated carbenium
ion intermediate.[7] Although early work by Taft et al. sug-
gested that the proton transfer was preceded by reversible
formation of a p-protonium complex,[8] this hypothesis has
been largely discounted.[7,9] Deviations from the general hy-
dration mechanism are rare but may occur in the cases of
particularly long-lived or short-lived carbenium ions. For ex-
ample, mechanisms involving rapid and reversible C=C
bond protonation followed by rate-limiting nucleophilic ad-
dition to the resulting carbenium ion have been documented
in the cases of highly stabilized carbenium ions.[10]
ꢀ
normal KIE in the case of sp3!sp2 rehybridization and an
inverse KIE in the case of sp2!sp3 rehybridization.
To probe for rehybridization of the C2’ carbon atom of
the cyclohexenyl moiety in the transition state of the turn-
over-limiting step of the triflic-acid-catalyzed hydroamina-
tion of 1a, we determined the a-secondary KIE resulting
from deuteration of the C2’ carbon atom of the cyclohexenyl
moiety employing deuterated isotopomer [2’-D1]1a. Owing
to the small magnitude of secondary KIEs[44] and to avoid
errors associated with variations in catalyst concentration
and temperature, the a-secondary KIE was determined
through a competition experiment. To this end, an approxi-
mate 1:1 mixture of 1a and [2’-D1]1a and a catalytic amount
of HOTf (5 mol%) in toluene was heated at 608C and ana-
lyzed periodically by LC-MS. The concentrations of 1a and
[2’-D1]1a were determined from the total conversion and
from the isotopic ratios 1a/
[2’-D1]1a and 2a/
E
Drawing from the analyses of Jencks,[11] Kresge et al. pos-
ited that preassociation or concerted mechanisms for alkene
hydration may be enforced by short carbenium ion life-
times.[12] On the basis of this analysis, Kresge et al. consid-
ered, but ultimately discounted, a preassociation pathway
for the acid-catalyzed hydration of trans-cyclooctene; how-
ever, Kresge et al. also suggested that preassociation path-
ways may be operative for the hydration of unstrained ole-
fins that generate secondary carbenium ions under dilute
acidic conditions.[12] Similarly, consideration of carbenium
ion lifetimes led Jencks et al.[13] and Herlihy[14] to propose
concerted pathways for the hydration of monosubstituted al-
kenes under dilute acidic conditions, although in neither
case were these pathways rigorously established.
of ln[1a] and ln[[2’-D1]1a] versus time were linear to about
ACHTUNGTRENNUNG
three half lives with observed rate constants of kobs =(2.19ꢂ
0.03) and (2.51ꢂ0.05)ꢁ10ꢀ3 sꢀ1, respectively (Figure 7),
which correspond to an inverse KIE of kD/kH =(1.15ꢂ0.03).
In a separate experiment, treatment of [2’-D1]1a (75ꢂ1%
[D1] by MS) with a catalytic amount of HOTf (5 mol%) at
858C in toluene for 48 h led to isolation of [7a-D1]2a (76ꢂ
1% [D1] by MS) as the exclusive deuterated isotopomer in
The mechanisms of the addition of hydrogen halides to al-
kenes and the addition of acetic acid to nonconjugated al-
kenes catalyzed by hydrogen halides and related Brønsted
acids have also been investigated.[15–32] These transforma-
tions typically occur with about 85% anti selectivity in the
case of nonconjugated acyclic alkenes and with >95% anti
selectivity in the case of nonconjugated cyclic alkenes.[16–25,27]
Hydrogen halide addition typically obeys the ternary rate
law: rate=k
droacetoxylation typically obeys the binary rate law: rate=
[alkene][HX].[17–19,26–29] Both AdE3 pathways involving con-
[alkene][HX]2, whereas the acid-catalyzed hy-
ACHTUNGTRENNUNG
*
Figure 7. First-order plots for the conversion of 1a to 2a ( ) and [2’-
kACHTUNGTRENNUG
D1]1a to [7a-D1]2a (&), catalyzed by triflic acid (5 mol%) in toluene at
608C.
ꢀ
ꢀ
certed C H and C X (X=halide or OAc) addition across
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Intramolecular Hydrofunctionalization of an Unactivated Cyclic Alkene
FULL PAPER
the C=C bond of the alkene[16,18,19,22,23,25,27,28] and/or stepwise
AdE2 pathways involving rate-limiting, halide-assisted proto-
nation of the alkene followed by rapid trapping of a tight
carbenium ion pair have been proposed to account for these
observations.[17,18,22,25,26,29] Initial formation of a p-protonium
complex has also been invoked,[16,24,25] but, as was the case
for alkene hydration, little direct evidence supports these
hypotheses.[30]
In contrast to the behavior of weaker Brønsted acids,
Roberts reported that the HOTf-catalyzed addition of [O-
D1]acetic acid to cyclopentene was non-stereoselective.[31] In
a separate study, Pasto et al. reported that the HOTf-cata-
lyzed addition of [O-D1]acetic acid to 2-butene occurred
with modest (57–72%) anti stereoselectivity and was accom-
panied by alkene isomerization and H/D exchange.[23] The
latter transformation was proposed to occur through an
AdE2 pathway involving reversible formation of a carbeni-
um ion pair that was trapped by acetic acid. The slight pref-
erence for the anti addition was attributed to steric shielding
of the syn face of the carbenium ion in the tight ion pair. In
comparison, the addition of hydrogen halides to cyclic and
acyclic vinyl arenes occurs with up to 90% syn selectivity in
low-polarity solvents, such as dichloromethane.[32] This be-
havior is in accord with a stepwise AdE2 pathway involving
turnover-limiting protonation to form a tight ion pair that
undergoes rapid collapse (syn addition) or rearrangement
followed by collapse (nonselective).
ed sulfonamide to the C3’ alkenyl carbon of 1a. Of the pos-
sible mechanisms that meet this requirement, stepwise path-
ways involving a solvationally equilibrated carbenium ion
(AdE2) or a tight ion pair are inconsistent with our experi-
mental observations, as is a stepwise preassociation pathway.
ꢀ
Because the regio- and stereoselectivity of the C N bond
formation in the conversion of 1a to 2a is largely predeter-
mined by the substrate geometry, protonation must occur
regio- and stereoselectively at the C3’ position of the cyclo-
hexene moiety on the face opposite that occupied by the di-
phenylethylsulfonamide group. Although delivery of
a
proton to the less sterically hindered face of the alkene is
reasonable, regioselective protonation of the electronically
unbiased C=C bond at C3’ without participation of the
pendant sulfonamide group appears unlikely. Preassociation
of the sulfonamide nitrogen atom and the alkene C2’ atom
prior to intermolecular proton transfer to C3’ in a manner
analogous to that suggested by Kresge and Chiang[12] ac-
counts for the regioselectivity of the proton transfer only if
the nitrogen atom is felt in the transition state for protona-
ꢀ
ꢀ
tion, at which point, the C H and C N bond formation
become concerted.[11]
Key to distinguishing between stepwise and concerted
mechanisms for the conversion of 1a to 2a is the a-secon-
dary KIE of kD/kH =(1.15ꢂ0.03) determined for the conver-
sion of [2’-D1]1a to [7a-D1]2a. This observation points to
ꢀ
significant C N bond formation in the turnover-limiting
Recently, the mechanisms of triflic acid catalyzed inter-
molecular alkene hydrofunctionalization with phenols and
protected amines has been investigated by a pair of DFT
studies.[33] In both cases, calculations predict a concerted,
step of the hydroamination and argues strongly against a
stepwise pathway involving turnover-limiting carbenium ion
formation. Employing the approximation of Streitwieser
et al.[45] of the Bigeleisen equation[47] and the representative
2
ꢀ
ꢀ
syn addition of the H X (X=N, O) bond of the nucleophile
C H stretching and bending frequencies for the sp carbon
across the C=C bond of the alkene through an eight-mem-
bered cyclic transition state in which triflic acid interacts
with both the alkene and the nucleophile.[33]
of cis-2-butene as a model for 1a and the sp3 methine
carbon of a secondary alcohol as a model for 2a,[48,49] we es-
timated a maximum a-secondary KIE for the conversion of
1a to 2a resulting from conversion of an alkene ground
state to a tetrahedral transition state of kD/kH ꢃ1.20 at
333 K. Consideration of calculated fractionation factors for
the H/D exchange between olefinic and aliphatic positions
predicts a similar value.[50] Conversely, because conversion
of 1a to 2a through turnover-limiting carbenium ion forma-
tion would occur without transition-state rehybridization,
such a process should occur without a significant a-secon-
dary KIE. Supporting this contention, the calculated
Mechanism of the acid-catalyzed conversion of 1a to 2a:
Our experimental observations rule out several potential
mechanisms for the acid-catalyzed conversion of 1a to 2a.
The absence of deuterium scrambling, alkene isomerization,
and/or incorporation of deuterium into unreacted starting
material in the acid-catalyzed reactions of isotopomers
[1’,3’-D2]1a, [N-D1]1a, and [2’-D1]1a argues strongly against
mechanisms involving rapid and reversible protonation/deu-
teronation of the C2’ or C3’ alkenyl carbon atoms followed
by turnover-limiting attack of the pendant sulfonamide on a
C2’ carbenium ion. Furthermore, the anti stereoselectivity
and the second-order rate law for the conversion of 1a to
2a rule out a mechanism analogous to those proposed by
Hosomi et al.[34] and Hartwig and Schlummer[4] involving in-
tramolecular proton transfer from a protonated sulfonamide
to the C3’ alkenyl carbon atom followed by trapping of the
resulting carbenium ion with the neutral sulfonamide
moiety.
fractionACTHNGUTRENNUaG tion factor of 1.179 for the H/D exchange between
a secondary carbenium ion and secondary alkyl moiety indi-
cates that fractionation factors between an olefinic and car-
benium hydrogen differ by only a few percent.[51]
Available experimental data regarding the a-secondary
KIEs of the Brønsted acid promoted addition of nucleo-
philes to alkenes are in accord with the analysis provided
above. For example, the thiocyanate-catalyzed isomerization
of [D2]maleic acid to [D2]fumaric acid displayed an inverse
KIE of kD/kH =1.17 (corrected for H/D exchange) at 258C,
attributed to turnover-limiting conjugate addition of thiocya-
nate to an O-protonated maleic acid.[52] In contrast, acid-cat-
alyzed hydration of a-deuteriostyrene[53] or 4,4-dideuterio-1-
We therefore considered mechanisms for the acid-cata-
lyzed conversion of 1a to 2a initiated by turnover-limiting,
irreversible intermolecular proton transfer from a protonat-
Chem. Eur. J. 2011, 17, 6170 – 6178
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6175

R. A. Widenhoefer and R. E. McKinney Brooner
phenyl-1,3-butadiene[54] displayed no detectable KIE, consis-
tent with turnover-limiting carbenium ion formation. Acid-
catalyzed hydrolysis of ethyl vinyl ether produced a small in-
verse a-secondary KIE of kD/kH =(1.036ꢂ0.004); however,
this effect was attributed to an inductive KIE rather than to
an a-secondary KIE.[55]
All of our experimental observations, including the
second-order rate law, activation parameters, inverse a-sec-
ondary KIE, and anti stereoselectivity are consistent with a
concerted mechanism for the conversion of 1a to 2a. Our
proposed mechanism is depicted in Scheme 1 for the DOTf-
intramolecular hydroamination of deuterated isotopomer
[3’-D1]1a revealed an inverse a-secondary KIE of kD/kH =
ꢀ
(1.15ꢂ0.03), consistent with significant C N bond forma-
tion in the turnover-limiting step of the hydroamination. All
of our experimental observations regarding the Brønsted
acid catalyzed conversion of 1a to 2a support a mechanism
involving concerted intermolecular transfer of a proton from
an N-protonated sulfonamide to the C3’ carbon atom of 1a
coupled with intramolecular anti addition of the pendant
sulfonamide nitrogen atom to the C2’ carbon atom. The
high anti stereoselectivity and the absence of deuterium
scrambling in the Brønsted acid
catalyzed intramolecular hydro-
alkoxylation of [1’,3’-D2]2b and
the hydroacyloxylation of [1’,3’-
D2]2c suggest that these trans-
formations occur through a sim-
ilar pathway.
Perhaps the most significant
implication of our study is that
the stereoselectivity of these
Brønsted acid catalyzed intra-
molecular hydrofunctionaliza-
tion processes is indistinguisha-
ble from that expected for an
outer-sphere transition-metal-
catalyzed pathway.[56] Further-
more, in the event that Brønst-
ed acids were generated stoi-
Scheme 1. Proposed mechanism of the DOTf-catalyzed cyclization of [N-D1]1a (Ts=tosyl).
catalyzed conversion of [N-D1]1a to [7ax-D1]2a. As has been
noted by Jencks,[11] preassociation is a necessary prerequisite
for concerted reaction pathways, and, as such, conversion of
[N-D1]1a to [7ax-D1]2a is likely initiated by formation of the
alkene–sulfonamide encounter complex I. Intermolecular
deuteron transfer from an N-deuterated sulfonamide to the
C3’ alkenyl carbon atom of [N-D1]1a in concert with an in-
tramolecular anti addition of the pendant sulfonamide nitro-
gen atom to the C2’ alkenyl carbon atom through transition
state TS-I would generate the N-deuterated sulfonamide
cation [7ax-D1]2a·DOTf. Intermolecular deuteron transfer
from [7ax-D1]2a·DOTf either to a second sulfonamide nitro-
gen atom or to the C3’ carbon atom of a second molecule of
[N-D1]1a would release [7ax-D1]2a and continue the catalytic
cycle (Scheme 1).
chiometrically from a metal precursor, the resulting acid-cat-
alyzed intramolecular hydrofunctionalization would appear
to conform to the second-order rate law: rate=[metal][sub-
strate], apparently consistent with a metal-catalyzed cycliza-
tion. The absence of positional isomerization or olefinic H/
D exchange would also appear consistent with a metal-cata-
lyzed transformation. As a result, it appears that strong cor-
roborating evidence and/or rigorous control experiments are
required to confidently discount the presence of Brønsted
acid catalyzed reaction pathways in metal-based alkene hy-
drofunctionalization processes.
Unknown at this time is the effect of the substrate struc-
ture on the mechanism of the Brønsted acid catalyzed intra-
molecular alkene hydrofunctionalization, such as in the
cases of acyclic alkenes or conjugated alkenes. Further stud-
ies in this area will probe the stereochemistry and mecha-
nisms of these permutations of acid-catalyzed alkene hydro-
functionalization.
Conclusion
We have shown that the Brønsted acid catalyzed intramolec-
ular hydrofunctionalization of a cyclohexenyl moiety with a
sulfonamide, alcohol, or carboxylic acid occurs with net anti
Experimental Section
ꢀ
addition of the H X (X=N, O) bond across the pendant
Methods and materials: For a general description of the chemicals and
the analytical methods that were used in this study see the Supporting In-
formation.
C=C bond of the cyclohexene moiety and without positional
isomerization or H/D exchange. Kinetic analysis of the in-
tramolecular hydroamination of the cyclohexenyl sulfona-
mide derivative 1a established a second-order rate law and
large negative entropy of activation. Kinetic analysis of the
General procedure for acid-catalyzed hydrofunctionalization
Synthesis of 2a:[35] To a solution of 1a (64.7 mg, 0.150 mmol) in toluene
(0.3 mL), triflic acid (0.7 mL, 7.5ꢁ10ꢀ3 mmol) was added through a sy-
6176
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6170 – 6178

Intramolecular Hydrofunctionalization of an Unactivated Cyclic Alkene
FULL PAPER
ringe. The resulting solution was heated at 608C for 3 h, cooled to room
temperature, and filtered through a plug of silica gel. The solvent was
evaporated under vacuum to give pure 2a (64.5 mg, 100%) as a white
solid. The aliphatic protons of 2a were unambiguous assigned on the
basis of combined 1H-1H COSY (800 MHz) and 1H-1H NOESY analysis
at 458C in CDCl3 (see the Supporting Information).[38] 1H NMR
(800 MHz, CDCl3, 458C): d=7.43 (d, J=8.0 Hz, 2H), 7.19 (t, J=8.0 Hz,
2H), 7.09 (t, J=8.0 Hz, 1H), 7.07–6.98 (m, 9H), 4.48 (d, J=11.1 Hz, 1H;
H2), 4.25 (d, J=11.1 Hz, 1H; H2), 3.78 (m, 1H; H7a), 2.95 (dt, J=10.4,
4.8 Hz, 1H; H3a), 2.49 (brd, J=14.4 Hz, 1H; H7eq), 2.32 (s, 3H), 1.58
(m, 1H; H7ax), 1.55–1.41 (m, 4H; H5, H6), 1.28–1.15 ppm (m, 2H; H4);
13C{1H} NMR (126 MHz, CDCl3, 258C): d=145.1, 143.8, 142.8, 134.2,
129.3, 128.5, 128.4, 127.6, 127.1, 126.7, 126.1, 125.7, 59.1, 58.2, 55.5, 44.3,
28.8, 25.5, 24.5, 21.5, 20.1 ppm.
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All remaining acid-catalyzed hydrofunctionalization reactions were per-
formed employing analogous procedures.
Kinetic experiments: Into a solution of 1a (488 mg, 1.13 mmol, 0.50m) in
dry toluene (2.25 mL) that had been pre-equilibrated at 62.58C triflic
acid (5.00 mL, 5.6ꢁ10ꢀ2 mmol, 25 mm) was added through a gas-tight sy-
ringe equipped with a stainless steel needle. The reaction mixture was
stirred and aliquots were periodically removed using a syringe, quenched
with saturated aqueous NaHCO3 solution, extracted with acetonitrile,
and analyzed by liquid chromatography equipped with an UV detector.
The conversion of 1a to 2a was quantitative and occurred without forma-
tion of intermediates or byproducts. Furthermore, analysis of stock solu-
tions of 1a and 2a revealed that the UV response factors of 1a and 2a
were not significantly different (ꢄ0.1%) over the concentration range
utilized in these experiments. For these reasons, the concentration of 1a
was determined from the integration of the peaks in the LC spectrum
corresponding to 1a and 2a according to the formula [1a]=0.50mꢀ{[1a]/
[1a]+[2a]}. A plot of ln[1a]t versus time was linear to about three half-
lives (Figure 4, Table 2), with an observed rate constant of kobs =(4.2ꢂ
0.1)ꢁ10ꢀ3 sꢀ1. Employing a similar procedure, observed rate constants for
the reaction of 1a with triflic acid were determined as a function of
[HOTf] and temperature.
a-Secondary KIE for the conversion of 1a to 2a: A mixture of 1a
(162 mg, 0.376 mmol) and [2’-D1]1a (74% [D1], 326 mg, 0.754 mmol) was
dissolved in toluene (2.25 mL). Mass spectral analysis of the resulting so-
lution revealed a 47.6:52.4 mixture of [D0]/[D1] isotopomers. The solution
was equilibrated at 59.58C and triflic acid (4.0 mg, 5.7ꢁ10ꢀ2 mmol) was
added. The resulting solution was stirred and aliquots were removed peri-
odically using a syringe, quenched with saturated aqueous NaHCO3 solu-
tion, extracted with acetonitrile, and analyzed by LC-MS for conversion
and isotopic abundance. The concentrations of 1a and [2’-D1]1a were de-
termined from total conversion, obtained by integration of the peaks in
the LC spectrum corresponding to 1a+
from the isotopic ratios 1a/[2’-D1]1a and 2a/
MS analysis of the corresponding LC peaks. Plots of ln[1a] and lnAHCTUNTGRENNUNG
A
ACHTUNGRTENUN[NG 7a-D1]2a and
A
ACHTUNGTRENNUNG
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rate constants of
k
obs =(2.19ꢂ0.03)ꢁ10ꢀ3 sꢀ1 and
k
obs =(2.51ꢂ0.05)ꢁ
10ꢀ3 sꢀ1, respectively (Figure 7), which correspond to an inverse KIE of
kD/kH =(1.15ꢂ0.03).
Acknowledgements
Acknowledgements is made to the NIH (GM-080422) for support of this
research and to the NCBC (2008-IDG-1010) for support of the Duke
University NMR facility. We thank Dr. Marina G. Dickens for obtaining
the X-ray crystal structure of 2a. R.E.M.B. thanks Duke University of a
Burroughs Wellcome fellowship.
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1
in the H-1H NOESY spectrum. As such, the more reliable determi-
nant to assign the H7ax and H7eq protons was the presence of a cross
peak between H3 and H7ax and the absence of a cross peak between
1
H3 and H7eq in the H-1H NOESY spectrum of 2a (see the Support-
ing Information).
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deuterium content of [N-D1]1a (ꢃ90% [D1]) was determined by
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toluene (0.033%), this sample also contained 7.9 mmol (ꢃ16 mm)
D2O.
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ACHTUNGTRENNUNGclization of substrates 1 occurs at lower temperature and with short-
er reaction time (608C, 3 h) with the same stereochemical outcome.
[37] X-ray data for 2a: monoclinic; P21/c; T=296 K; a=8.8385(10), b=
26.705(3), c=9.4913(11) ꢆ; b=94.690(8)8; V=2232.8(5) ꢆ3; Z=4,
RACHTUNGTRENNUNG
[F2>2s(F2)]=0.042; wR(F2)=0.138. CCDC-798744 contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[38] We were unable to assign the relative configuration of [3a,7eq-D2]2a
ꢀ
ꢀ
from the H7a H7eq and H7a H7ax three-bond coupling constant as
Received: October 30, 2010
Published online: April 19, 2011
has been previously reported.[35] The equatorial conformation of the
6178
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