A mechanistic analysis of the Rh-catalyzed intramolecular C-H amination reaction

Article abstract of DOI:10.1016/j.tet.2008.11.073

A detailed mechanistic investigation of the intramolecular dirhodium tetracarboxylate-catalyzed sulfamate ester C-H amination reaction is presented. These studies provide support for the formation of a sulfamate-derived iminoiodinane, which reacts rapidly

Full text of DOI:10.1016/j.tet.2008.11.073

Tetrahedron 65 (2009) 3042–3051
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A mechanistic analysis of the Rh-catalyzed intramolecular C–H
amination reaction
*
Kristin Williams Fiori, Christine G. Espino, Benjamin H. Brodsky, J. Du Bois
Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A detailed mechanistic investigation of the intramolecular dirhodium tetracarboxylate-catalyzed sulfa-
mate ester C–H amination reaction is presented. These studies provide support for the formation of
a sulfamate-derived iminoiodinane, which reacts rapidly with the rhodium catalyst to generate a ni-
trenoid-type oxidant. Reactivity patterns, Hammett analysis, kinetic isotope measurement, and a cyclo-
propane clock experiment are indicative of a concerted, asynchronous transition structure in the
product-determining C–H insertion event.
Received 12 November 2008
Accepted 19 November 2008
Available online 27 November 2008
Ó 2008 Published by Elsevier Ltd.
1. Introduction
mechanistic studies described in this work have focused exclusively
on reactions with these materials.
Recent advances in the design of catalytic methods for the
intramolecular amination of C–H bonds have provided unique tools
for the synthesis of complex amine-derived products.1 Such
chemistries are marked by their efficiency and selectivity, and
conveniently make available several different heterocyclic struc-
tures from simple starting materials (Fig. 1).2,3 In addition to
identifying new substrates and advancing new protocols and cat-
alysts for C–H amination, we have engaged in mechanistic studies
aimed at revealing the nature of the active oxidant and identifying
the steps in the catalytic cycle that precede the C–H insertion
event.4,5 Herein, we provide experimental evidence that supports
the following conclusions: (1) the reactive oxidant is best described
as a Rh-bound nitrene; (2) C–H functionalization occurs through
a concerted, asynchronous pathway; and (3) the requisite con-
densation between the substrate and terminal oxidant is largely
disfavored. These findings have added to our general un-
derstanding of metal-mediated C–H amination reactions and have
been instrumental for the continued evolution of such methods.
In our earliest reports, the stereospecific oxidation of enantio-
enriched 3ꢀ C–H centers was highlighted as a defining characteristic
of this method.3a,e,8 Such a property is suggestive of a mechanism
involving the concerted orchestration of C–N bond formation and
C–H bond cleavage, in accord with prior work of Mu¨ller (Fig. 2).5a
The stereospecific nature of the amination process is analogous to
that of Rh-catalyzed carbene insertion, for which a concerted,
asynchronous pathway leading to C–C bond formation is generally
accepted.9,10 Stereospecific modification of a 3ꢀ C–H bond, however,
is insufficient evidence to discount a stepwise process for oxidation
that occurs by initial homolytic C–H abstraction followed by rapid
radical rebound.11 Additional data, including C–H bond reactivity
trends, cyclopropane clock experiments, kinetic isotope effect (KIE)
measurements, and Hammett analysis are needed to distinguish
between these two limiting pathways. Thus, in order to examine in
greater detail the sulfamate C–H insertion event, these experiments
were performed.
For a reaction such as sulfamate ester oxidation, intramolecular
competition experiments offer
a straightforward method for
delineating the rank order of C–H bond reactivity. Such data are
invariant of the reaction kinetics and the rate-limiting step in the
catalytic cycle. Accordingly, a series of sulfamate derivatives was
prepared having two chemically distinct C–H bonds positioned at
2. Results and discussion
2.1. Reactivity trends
Rhodium-catalyzed C–H amination has been demonstrated to
function with carbamate, urea, guanidine, sulfamate, sulfamide,
and sulfonamide (not shown) substrates (Fig. 1).6,7 Due to the
general effectiveness of sulfamate esters for C–H insertion, the
O
O
NR
O
HN
O
O
O
HN
O
NR
[O]
S
S
H
NH2
HN
O
HN NR HN NH
C
catalytic
Rh (O CR)
4
intramolecular C–H oxidation
2
2
* Corresponding author. Tel.: þ1 650 724 4557; fax: þ1 650 725 0259.
E-mail address: jdubois@stanford.edu (J. Du Bois).
Figure 1. Heterocycle synthesis through Rh-catalyzed C–H amination.
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.11.073

K.W. Fiori et al. / Tetrahedron 65 (2009) 3042–3051
3043
‡
Each sulfamate ester in Table 1 was subjected to oxidative cy-
clization using 2 mol % of a dimeric Rh(II)-tetracarboxylate catalyst
(Rh2(OAc)4, Rh2(O2CtBu)4, Rh2(esp)2, Rh2(O2CCPh3)4), 1.1 equiv of
PhI(OAc)2, and MgO.12,13 In all cases, oxathiazinane heterocycles
were formed exclusively and neither of the five-membered ring
sulfamidates was obtained. Product ratios were determined by 1H
NMR analysis of the unpurified material and, as is apparent from
these findings, selectivity for the two oxathiazinane isomers varied
dramatically depending on the catalyst employed. Comparing the
information gathered from experiments with Rh2(OAc)4, a qualita-
tive rate scale for C–H amination can be drawn as follows:
3ꢀ>etherealwbenzylic>2ꢀ>>1ꢀ. Primary methyl C–H bonds are at
the bottom end of the reactivity spectrum and, in fact, we have
witnessed in only one rare example the product of –CH3 insertion.
Three additional observations merit comment: (1) general re-
activity trends parallel those observed in Rh-catalyzed carbenoid
insertions; (2) the connectivity of the sulfamate can effect the
product outcome albeit to a small, yet still discernible, degree (cf.
entries 2 and 8); and (3) the catalyst structure can influence
product selectivity. This latter point has important mechanistic
implications and provides the most compelling evidence for an
active oxidant that is Rh-bound. Results with Rh2(O2CCPh3)4 are
striking in this regard (for example, entries 1, 2, 3, and 5) and
suggest that remote steric effects between the substrate and cata-
lyst framework can be employed to direct reaction chemo-
selectivity.14,15 As a general rule, insertion at benzylic centers is
strongly disfavored in reactions promoted by Rh2(O2CCPh3)4.16,17
As the same oxidative protocols for C–H bond amination serve
effectively for olefin aziridination, the matter of chemoselectivity in
cyclization reactions of unsaturated sulfamates manifests.18 A small
collection of differentially configured alkene substrates was fash-
ioned to examine this question (Table 2). In three cases (entries
1–3), C–H oxidation could occur at an allylic center to give the
corresponding oxathiazinane product. Alkene aziridination, on the
other hand, would afford a fused 7,3-bicyclic ring system. As in-
dicated by these collective data, aziridination is, at a minimum,
O
O
O
S
N
R2
S
S
HN
O
concerted C–H
insertion
O
O
R2
RhLn
R1
O
O
R1
H
S
[O]
H2N
O
R2
O
O
R1
O
S
N
R2
HN
O
C–H abstraction/
radical rebound
O
RhLn
O
R2
R1
R1
H
Figure 2. Putative mechanisms for Rh-catalyzed C–H insertion.
the
g
and g0 carbon centers (Table 1). The ratio of the product
heterocycles formed in the oxidation reaction is, in effect, a mea-
sure of the rate at which each C–H center can engage the active
oxidant. These types of experiments can be used to query the in-
fluence of substituent effects (steric or electronic) and catalyst
structure on chemoselectivity.
Table 1
Catalyst influence on reaction chemoselectivity
2 mol%
catalyst
O
O
O
O
O
O
S
S
S
H2N
R1
O
HN
R1
O
O
NH
R2
+
R2
R2
R1
PhI(OAc)2
γ
γ'
γ
γ'
MgO, CH2Cl2
b
Entry
1
Substrate
Catalysta
g/
g0
O
O
Rh2(OAc)4
1:1.5
1:1.5
1:7
Rh2(O2CtBu)4
Rh2(esp)2
S
H2N
Ph
O
Me
Me
Rh2(O2CCPh3)4
1:14
O
O
S
Rh2(OAc)4
Rh2(O2CCPh3)4
1:1
1:15
H2N
O
2
3
4
5
Ph
OMe
nPr
O
O
Table 2
S
C–H insertion versus alkene aziridination
Rh2(OAc)4
Rh2(O2CCPh3)4
8:1
1:1.5
H2N
O
2 mol%
catalyst
O
O
O
O
O
O
Ph
S
S
S
O
O
H2N
O
HN
O
R
N
O
+
S
Rh2(OAc)4
Rh2(O2CCPh3)4
1:20
1:4.5
H2N
Me
O
Me
PhI(OAc)2
R
n
R
n
n
MgO, CH2Cl2
I
A
Me
O
O
S
Rh2(OAc)4
Rh2(O2CCPh3)4
1:11
1:14
Catalysta
I/Ab
H2N
nBu
O
Entry
1
Substrate
OMe
Rh2(OAc)4
Rh2(esp)2
Rh2(O2CCPh3)4
Rh2(NHCOCF3)4
1:1
O
O
O
O
1:1.5
1:20
1:4
S
H2N
O
S
Rh2(OAc)4
1:2
1:2
1:6
H2N
O
Me
Me
6
7
Rh2(O2CtBu)4
Rh2(O2CCPh3)4
O
O
Rh2(OAc)4
Rh2(esp)2
Rh2(O2CCPh3)4
Rh2(NHCOCF3)4
2:1
1:1
1:5
1:2
S
O
O
H2N
O
2
3
S
H2N
O
Rh2(O2CtBu)4
Rh2(O2CCPh3)4
1:1
1:3.5
Me
Me
Rh2(OAc)4
Rh2(esp)2
Rh2(O2CCPh3)4
Rh2(NHCOCF3)4
1:1
Me
O
O
1:2.5
1:20
1:4
S
S
OMe
Me H2N
O
Rh2(OAc)4
Rh2(O2CCPh3)4
1:3
1:10
O
O
S
Rh2(OAc)4
Rh2(esp)2
Rh2(O2CCPh3)4
1:1
1:1
1:7
H2N
Ph
O
O
O
8
4
H2N
O
OMe
a
a
Reactions performed in CH2Cl2 at 23 ꢀC using 1.1 equiv of PhI(OAc)2, 2.3 equiv of
MgO, and 2 mol % of the indicated catalyst.
Reactions performed in CH2Cl2 at 23 ꢀC using 1.1 equiv of PhI(OAc)2, 2.3 equiv of
MgO, and 2 mol % of the indicated catalyst.
b
Product ratios are based on integration of the 1H NMR spectrum of the un-
b
Product ratios are based on integration of the 1H NMR spectrum of the un-
purified reaction mixture and are not corrected for statistics.
purified reaction mixture.

3044
K.W. Fiori et al. / Tetrahedron 65 (2009) 3042–3051
competitive with allylic amination.19 Only in one case, which
utilizes Rh2(OAc)4 as catalyst, is a slight bias noted for the six-
membered oxathiazinane product (entry 2). In agreement with
earlier findings, different catalysts alter product ratios in these
types of competition experiments. For reasons not entirely appar-
ent, reactions performed with Rh2(O2CCPh3)4 are strongly biased
toward alkene aziridination. Remarkably, the predilection for
alkene oxidation by Rh2(O2CCPh3)4 is manifest even in the tris-
homoallylic sulfamate (entry 4), a reaction that affords an unusual
eight-membered ring bicycle.20 It is worth noting that oxidation of
cis- and trans-alkene derivatives (entries 2 and 3) is stereospecific,
as would be expected for a concerted, electrophilic oxidation
process.
O
O
O
O
O
O
S
S
S
[O]
H2N
O
HN
O
O
NH
+
Ar
Ph
2
X
Ph
Ar
0.6
0.4
0.2
0
y = –0.5540x + 0.0446
R2 = 0.9575
X
+
Ar/Ph
Homoallylic sulfamate 1 presents an alternative type of com-
petition substrate for assessing reactivity differences between an
alkene and a C–H bond (Fig. 3). With this starting material, all four
catalysts employed favor aziridine production, Rh2(O2CCPh3)4
affording the highest degree of selectivity. In these experiments,
small changes in the diastereochemical outcome of the aziridina-
tion event as a function of catalyst structure are also noted.
The results from competition studies highlighted in Tables 1 and
2 and Figure 3 should provide a useful guide for future substrate
designs. Clear reactivity differences between sp3 C–H bonds exist
that are attributable to electronic effects (vide infra); however, the
influence of steric forces between substrate and catalyst can be
quite pronounced and will, in many cases, supersede intrinsic
electronic biases. Next generation catalyst designs will seek to ex-
ploit this knowledge. Altogether, the general trends in reactivity
p-OMe –0.78 3.0 : 1.0
-0.2
-0.4
-0.6
CH3
Br
CF3
NO2
–0.31 1.7 : 1.0
0.15 1.0 : 1.1
0.61 1.0 : 1.5
0.79 1.0 : 3.0
-1
-0.75
-0.5
-0.25
0
+
0.25
0.5
0.75
1
Figure 4. Hammett analysis of Rh2(oct)4-catalyzed C–H amination.
degree of partial positive charge at the reacting carbon center. An
improved fit of the data against sþ rather than sp values indicates
that cationic charge stabilization (d
þ) at the carbon undergoing
oxidation is due in part to a resonance contribution.24 Such findings
correlate nicely with our observed reactivity trends. Notably, the
between C]C and s-C–H bonds appear to mirror largely those of
Rh-promoted diazoalkene processes, and intimate that the reactive
oxidizing species are indeed analogous (i.e., Rh-bound carbene vs
Rh-bound nitrene).9 Hammett analysis, KIE data, and cyclopropane
clock studies, as described below, support such speculation.
calculated
r-value is similar to that measured in both our lab and
Mu¨ller’s for intermolecular C–H amination (
r
¼ꢁ0.73 and ꢁ0.90,
respectively)4,5a,b and for both intra- and intermolecular Rh-
catalyzed carbene insertion (
r
¼ꢁ0.78 and ꢁ1.27, respectively).21,25
Hammett analysis of the sulfamate oxidation reaction is thus in
accord with an asynchronous, concerted transition structure, as
proposed for Rh-carbenoid C–H insertion.9,10
2 mol%
catalyst
O
H2N
O
O
O
HN
O
O
O
O
O
N
S
S
S
Me
+
Me
PhI(OAc)2
MgO, CH2Cl2
Me
Me
Me
Me
H
1A
H
2.3. Kinetic isotope effect and radical-clock studies
1
1I
6–9:1 cis/trans
selectivity
1 : 6 1I/1A
1 : 6
1 : 20
Rh2(OAc)4
Rh2(esp)2
Rh2(O2CCPh3)4
Rh2(NHCOCF3)4
The measured kinetic isotope effect (KIE) for the Rh-catalyzed
amination reaction provides additional support for a concerted
oxidation event. As with the Hammett analysis, the magnitude of
the KIE was easily determined through an intramolecular compe-
tition experiment. Mono-deuterated sulfamate 3 was prepared and
when subjected to cyclization under Rh2(OAc)4 catalysis yielded
a 1.9ꢂ0.2:1 ratio of oxathiazinane heterocycles (Fig. 5). Analysis of
the product mixture by 13C NMR provided the most straightforward
and reproducible method for establishing this value.26 A KIE of
1.9ꢂ0.2 is comparable to those found for rhodium-catalyzed car-
bene C–H insertion reactions, determined to be between 1.2 and 2.1
depending on the catalyst and substrate employed.27 Additionally,
carbethoxynitrene (generated upon base treatment of N-(p-nitro-
benzenesulfonoxy)urethane) reacts with an equimolar mixture of
cyclohexane and cyclohexane-d12 to give a KIE¼1.5ꢂ0.2.28 By
contrast, Ru-based intermolecular C–H amination methods, which
are generally thought to occur by way of a radical-rebound
1 : 4.5
Figure 3. Alkene aziridination out-competes 3ꢀ C–H bond insertion.
2.2. Hammett studies
The electronic nature of the transition structure for C–H ami-
nation was further investigated by conducting intramolecular
competition experiments with substituted diaryl derivatives 2
(Fig. 4).21 Selectivity for oxidation of one of the two sets of benzylic
C–H bonds occurs in the product-determining step and thus the
ratio of isomeric oxathiazinanes offers a direct measure of kAr/kPh
.
The advantage of performing a Hammett analysis in this manner is
that it renders any prior knowledge of the reaction kinetics un-
necessary (i.e., which step is rate-determining step). Accordingly,
sulfamates having two electronically disparate benzylic sites
suitably disposed for oxathiazinane formation were subjected to
Rh2(oct)4-catalyzed oxidation.22 Product ratios were evaluated by
1H NMR integration of the spectra taken on unpurified material and
by HPLC analysis, and from this data log(kAr/kPh) was determined.
Plotting these values against sþ parameters for each substituent
2 mol%
Rh2(OAc)4
O
O
O
O
S
S
H
D
O
O
HN
O
HN
O
+
S
Ph
O
NH2
PhI(OAc)2
MgO
Ph
Ph
D
H
3
k /k = 1.9( 0.2)
H
D
gives a calculated
r
-value of ꢁ0.55.23 Such a small, negative number
Figure 5. Kinetic isotope effect measured in competition experiment.
is consistent with a picture of the transition structure having some

K.W. Fiori et al. / Tetrahedron 65 (2009) 3042–3051
3045
mechanism, furnish KIEs of 6–12.5c,e,29 A recent theoretical analysis
of our related carbamate insertion reaction supports a three-cen-
tered transition structure for the nitrenoid insertion event.30–32
Rhodium-catalyzed amination with a cyclopropyl clock-derived
sulfamate provides the final, and arguably the most compelling,
piece of evidence to differentiate between a radical-rebound process
and a concerted, asynchronous insertion event.33 Guided by work
of Newcomb, phenyl-substituted cyclopropane 4 was prepared
(Fig. 6).11a The choice of this particular clock follows from a report
that describes reactions of dimethyldioxirane with (trans-2-phe-
nylcyclopropyl)ethane.34 The absence of cyclopropane ring opening
in such experiments argues for a concerted C–H hydroxylation
event. Based on these data, we assume that the rate constant for
fragmentation of the cyclopropylcarbinyl radical derived from 4 is
O
H2N
O
O
O
HN
O
O
S
S
1 equiv
1 equiv
Me
Me
Me
Me
Me
Me
2 mol%
7
6
Rh2(OAc)4
1:1 mixture at
10% conversion
+
+
PhI(OAc)2
MgO
O
H2N
O
O
O
HN
O
O
S
S
Me
Me
Me
Me
8
9
Figure 7. Competition results show that C–H insertion is not the rds.
on the order of 7ꢃ1010 sꢁ1 35
.
If a C–H abstraction/radical-rebound
first data point, measured within 40 s of initiating the reaction,
shows w10% product formation. Remarkably, all five runs at dis-
parate catalyst loads afforded an identical amount of oxathiazinane
11 between 30 and 100 s. While increasing the amount of
Rh2(O2 Bu)4 did improve overall conversion, the data are quite
clear that this process is zero order in catalyst in the initial reaction
mechanism was operative in the Rh-catalyzed process, the lifetime
of the putative radical would haveto be exceedingly short (w200 fs).
In both the intramolecular cyclization of 4 and in a related in-
termolecular C–H amination reaction, we have observed none of the
olefin-containing products that would be expected from cyclopro-
pane fragmentation.4 Although it is possible to employ radical clocks
that fragment/rearrange at faster rates, we feel that this data to-
gether with the Hammett r-value and KIE strongly implicate a
concerted, asynchronous pathway for C–H insertion in the Rh-
catalyzed amination process.
t
burst.37
Further kinetic experiments were conducted to establish the
dependence of the reaction rate on substrate concentration. Cata-
lyst loading was fixed at 2 mol % (with respect to PhI(OAc)2) and
[10] was varied between 0.0785 M and 0.55 M.38 Observed rate
constants (kobs) were determined at each substrate concentration
using data recorded between 5 s and 35 s of initiating the reaction.
Each trial was repeated twice and an average kobs value was
calculated. A plot of kobs versus substrate concentration gives
a straight line, indicative of reaction having first-order dependence
on sulfamate 10 (Fig. 9).
2 mol%
Rh2(OAc)4
O
HN
O
O
91% isolated yield
S
O
O
O
NH2
no ring-opened
S
Ph
PhI(OAc)2
MgO
products observed
Ph
H
4
H
5
Our attempts to measure reaction rates as a function of oxidant
concentration were, at first, unsuccessful. It appears that deleteri-
ous side reactions occur when [PhI(OAc)2] exceeding 0.17 M is used
to conduct the amination reaction. Thus, an accurate assessment of
the product conversion over a wide enough [PhI(OAc)2] could not
be made. Instead, reactions were performed under pseudo-first-
order conditions by employing a ninefold excess of substrate 10 and
by recording the formation of product 11 over the reaction course.
Plotting ln([substrate]/[substrate]0) versus time yielded a straight
Figure 6. C–H amination of a radical-clock containing substrate.
2.4. Kinetics analysis
Having examined the reactivity properties of the oxidizing
species, we wished to understand the detailed steps leading to the
formation of this intermediate. Competition experiments per-
formed with equimolar amounts of sulfamates 6 and 8 yielded a 1:1
mixture of the two oxathiazinanes (Fig. 7), in stark contrast to the
20:1 selectivity recorded for intramolecular 3ꢀ versus 2ꢀ C–H oxi-
dation (see entry 4, Table 1). The disparity between the inter- and
intramolecular competition reactions indicates that the rate-de-
termining step (rds) in this catalytic process occurs prior to C–H
insertion.
0.5–5 mol%
O
O
Rh2(O2CtBu)4
S
Me
HN
O
O
O
S
NH2
Me
O
PhI(OAc)2
CD2Cl2
Me
Me
11
We have analyzed the kinetic order of the catalyst, substrate,
and PhI(OAc)2 by measuring reaction rates as a function of con-
centration for each starting material. In these studies, reactions
were performed at 23 ꢀC in CH2Cl2 or CD2Cl2 using isoamyl sulfa-
mate 10, Rh2(O2CtBu)4, and PhI(OAc)2 in the absence of any added
MgO (Fig. 8). There are several advantages to this set of reaction
conditions for mechanistic inquiry, foremost of which is that oxi-
dation of 10 proceeds to high conversion (>90%) without having to
include an insoluble salt, MgO.36 In addition, Rh2(O2CtBu)4 has
excellent solubility in halogenated solvents. As such, the time
course of the homogeneous reaction could be monitored using 1H
NMR spectroscopy. To ensure the accuracy of these measurements,
product formation was also analyzed by quenching small aliquots
of the reaction mixture and determining reaction conversion by
HPLC.
10
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
0.5 mol% catalyst
1.0 mol%
2.0 mol%
4.0 mol%
5.0 mol%
Initial rates for C–H amination were investigated over a 10-fold
catalyst concentration range (0.5–5.0 mol %), data for which are
shown in Figure 8. In these experiments, a solution of oxidant was
added in a single charge to a mixture of catalyst and sulfamate. The
0
100
200
time (seconds)
300
400
500
Figure 8. Oxathiazinane 11 formation versus time at different catalyst loadings.

3046
0.60
K.W. Fiori et al. / Tetrahedron 65 (2009) 3042–3051
2 mol%
Rh2(OAc)4
O
H2N
O
O
O
N
O
O
O
HN
O
O
PhI(OAc)2
S
PhI
Ph
S
S
y = –0.8961x – 0.0223
2 = 0.9586
R
0.50
0.40
0.30
0.20
0.10
0.00
CH2Cl2
>95% conv.
KOH, MeOH
Ph
Ph
14
15
16
Ph
O
H2N
O
O
O
N
O
O
O
N
O
O
PhI(OAc)2
PhSMe
S
PhI
Ph
S
S
S
Me
Ph
Ph
15
14
17
not observed by 1H NMR
Figure 11. Control experiments with iminoiodinane starting material.
0.00
0.10
0.20
0.30
[sulfamate] (M)
0.40
0.50
0.60
At present, our analysis of the reaction mechanism has been
unable to identify the specific rate-determining step in the cata-
lytic reaction cycle. Despite the absence of observable amounts of
iminoiodinane 15 in control experiments, its intermediacy is
strongly inferred from the recorded data. We note, however, that
it is possible to draw more than one path by which 15 may be
generated and that an intermediate substrate$oxidant complex
may be an equally competent reactant under the reaction condi-
tions. Assuming for now that iminoiodinane 15 is indeed formed,
its coordination to the Rh center must be fast relative to its re-
version to starting material (or an intermediate species) in order
to account for the zero-order dependence of [Rh2(O2CR)4] on the
initial reaction rate. Following the first 60–100 s, we speculate that
the increasing concentration of RCO2H must increase the rate of
iminoiodinane protonolysis (i.e., 15/14) so as to alter the initial,
simplified rate expression. A change in the concentration of active
catalyst is also likely responsible for the kinetics data recorded in
Figure 8.2e,43 Further investigations are warranted to assess ad-
ditional details of this complex reaction process.
Figure 9. Reaction rate has first-order dependence on [sulfamate].
line for each of the three trials, thereby confirming that reaction
rates have a first-order dependence on oxidant.
From the kinetic studies, an initial rate law for the C–H amination
reaction may be drawn as, rate¼k[substrate ]1[oxidant ]1[catalyst]0.
One possible mechanism that conforms to this rate expression is
depicted in Figure 10. Generation of a substrate$oxidant complex
could take on several forms including iminoiodinane 12. Pre-
sumably, under the conditions of the reaction, a small amount of 12
is generated and reacts rapidly with the Rh catalyst. Such a scenario
is consistent with a zero-order dependence of Rh2(O2CtBu)4 on the
initial reaction rate. Several questions arise from this mechanistic
postulate: (1) is the iminoiodinane 12 a chemically competent in-
termediate on the catalytic pathway for C–H insertion; (2) is such an
intermediate observable upon mixing sulfamate and oxidant; (3)
what is the rate-limiting step in the production of 12? We have
prepared, isolated, and characterized iminoiodinane 15 and have
demonstrated that this species does indeed react rapidly (<30 s at
23 ꢀC) with 2 mol % Rh2(OAc)4 to give the corresponding oxathia-
zinane (>95% conversion, Fig. 11).39 Such a finding is not surprising
in light of earlier work by Mu¨ller using NsN]IPh for Rh-catalyzed
intermolecular C–H amination.5a,b The inability to observe any of 15
in a CD2Cl2 solution of sulfamate 14 and PhI(OAc)2 was, however,
quite unexpected. Apparently, the equilibrium between 14þ
PhI(OAc)2/15 (or an intermediate species) greatly favors the re-
actants and none of the iminoiodinane is detectable within the
limits of 1H NMR.40,41 The addition of PhSMe to this mixture results
in the gradual formation (w24 h) of sulfylimine 17, thus providing
an indirect confirmation for the generation of iminoiodinane under
these reaction conditions (Fig. 11).42 Although it is reasonable to
speculate that Rh2(O2CR)4 could promote the formation of 15 (by
activating the oxidant, for example), its zero-order dependence in
the rate law does not accord with such a proposal.
3. Conclusions
Rhodium-catalyzed intramolecular C–H amination represents
a general method for the preparation of amine-derived heterocy-
cles. Our interest in understanding reactivity trends and other
phenomena associated with this process has driven our efforts to
dissect the reaction mechanism. A combination of data collected
through the use of substrate probes and competition experiments
leads to the conclusion that the active oxidizing species is best
described as a Rh-bound nitrene and that C–H insertion is likely
a concerted, asynchronous event. Reaction kinetics analysis has
resulted in the unexpected discovery that the initial rate of product
formation is independent of catalyst concentration. This result has
led us to postulate a mechanism in which the formation of
a sulfamate$oxidant complex (i.e., an iminoiodinane) is rate limit-
ing in the initial reaction burst. The details of the events that ensue
beyond the initiation of the amination reaction are most intriguing;
unraveling these mysteries should reveal clues for evolving further
C–H amination technology.
–AcOH
–AcOH
OAc
I
O
O
O
O
NH2
O
O
N IPh
S
S
+
S
4. Experimental procedures
4.1. General
RO
N
Ph
RO
RO
H
iminoiodinane
PhI(OAc)2
12
fast
All reagents were obtained commercially unless otherwise noted.
Reactions were performed using oven-dried glassware under an at-
mosphere of nitrogen. Air and moisture sensitive liquids and solu-
tions were transferred via syringe or stainless steel cannula. Organic
solutions were concentrated under reduced pressure (ca. 15 mmHg)
by rotaryevaporation. Dichloromethane and acetonitrilewere freshly
distilledfrom CaH2 immediatelypriortouse. N,N-Dimethylacetamide
O
O
NH
C–H insertion
–PhI
O
O
N
O
O
S
O
S
S
RhLn
RO
RhLn
RO
N
Me
IPh
Rh-nitrene
Me
11
13
Figure 10. Proposed mechanism for Rh-nitrene formation.

K.W. Fiori et al. / Tetrahedron 65 (2009) 3042–3051
3047
(DMA) was dried over 4 Å molecular sieves and stored under an at-
mosphere of nitrogen. Chromatographic purification of products was
accomplished using forced-flow chromatography on EM Science
1H, J¼10.1, 5.6 Hz), 3.34 (s, 3H), 2.83–2.69 (m, 2H), 2.14–1.94 (m,
4H) ppm; 13C NMR (CDCl3, 100 MHz)
141.0, 128.5, 128.4, 126.1,
3276, 2931,
d
81.7, 68.3, 58.5, 36.5, 34.1, 31.1 ppm; IR (thin film)
n
Geduran silica gel 60 (35–75
mm). Thin-layer chromatography (TLC)
1496, 1455, 1361, 1180, 1108, 917 cmꢁ1; HRMS (ESþ) calcd for
C12H19NO4S 273.1035, found 296.0938 (MNaþ).
was performed on EM Science silica gel 60 F254 plates (250
mm). Vi-
sualization of the developed chromatogram was accomplished by
fluorescence quenching and by staining with ethanolic anisaldehyde,
aqueous potassium permanganate, or aqueous ceric ammonium
molybdate (CAM) solution. Product melting points were acquired on
a Thomas Hoover Capillary Melting Point apparatus.
4.2.1.3. 1-Phenyloctan-3-yl sulfamate (Table 1, entry 3). Purified by
chromatography on silica gel (4:1 hexanes/EtOAc); white solid
(75%): TLC Rf¼0.21 (4:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d
7.33–7.26 (m, 2H), 7.23–7.18 (m, 3H), 4.81 (br s, 2H), 4.64 (quint,1H,
Nuclear magnetic resonance (NMR) spectra were acquired on
a Varian Mercury spectrometer operating at 400 and 100 MHz for
1H and 13C, respectively, or on a Varian Inova spectrometer oper-
ating at 500 and 125 MHz for 1H and 13C, respectively, and are
referenced internally according to residual solvent signals. Data for
J¼6.0 Hz), 2.81–2.67 (m, 2H), 2.08–2.01 (m, 2H), 1.82–1.69 (m, 2H),
1.42–1.24 (m, 6H), 0.89 (t, 3H, J¼6.8 Hz) ppm; 13C NMR (CDCl3,
100 MHz) d 141.1, 128.5, 128.3, 126.1, 84.7, 35.5, 34.0, 31.5, 31.1, 24.4,
22.4, 14.0 ppm; IR (thin film) n 3374, 3285, 3063, 3028, 2955, 2931,
2862, 1706, 1603, 1556, 1496, 1455, 1359, 1183, 1031, 919, 801 cmꢁ1
;
1H NMR are recorded as follows: chemical shift (
d, ppm), multi-
HRMS (ESþ) calcd for C14H23NO3S 285.1399, found 308.1298 (MNaþ).
plicity (s, singlet; br s, broad singlet; d, doublet; br d, broad doublet;
t, triplet; q, quartet; quint, quintet; sept, septet; m, multiplet), in-
tegration, coupling constant (Hz). Data for 13C NMR are reported in
4.2.1.4. 2-Methylheptan-4-yl sulfamate (Table 1, entry 4). Purified
by chromatography on silica gel (5:1 hexanes/EtOAc); white solid
(73%): TLC Rf¼0.22 (4:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
terms of chemical shift (d, ppm). Infrared spectra were recorded on
a Thermo Nicolet IR300 spectrometer and are reported in terms of
frequency of absorption. Sample preparation was done either as
a thin film on a NaCl salt plate or as a KBr pellet. High-resolution
mass spectra were obtained from the Vincent Coates Foundation
Mass Spectrometry Laboratory at Stanford University.
d 5.13 (br s, 2H), 4.67–4.61 (m, 1H), 1.78–1.62 (m, 4H), 1.47–1.34 (m,
3H), 0.95–0.90 (m, 9H) ppm; 13C NMR (CDCl3, 100 MHz)
36.5, 24.3, 22.8, 22.4, 17.9, 13.9 ppm; IR (thin film) 3375, 3287,
2961, 2875, 1559, 1468, 1359, 1184, 921 cmꢁ1
d 83.8, 43.1,
n
.
4.2.1.5. 1-Methoxynonan-3-yl sulfamate (Table 1, entry 5). Purified
by chromatography on silica gel (2:1 hexanes/EtOAc); colorless oil
(70%): TLC Rf¼0.36 (2:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
4.2. Experimental procedure and characterization data for
sulfamate esters (Tables 1 and 2)
d
4.99 (br s, 2H), 4.72 (quint, 1H, J¼6.1 Hz), 3.57 (dt, 1H, J¼9.9,
4.2.1. General procedure
6.5 Hz), 3.47 (dt, 1H, J¼9.9, 5.6 Hz), 3.41 (s, 3H), 1.95 (q, 2H,
J¼6.0 Hz), 1.80–1.65 (m, 2H), 1.42–1.24 (m, 8H), 0.88 (t, 3H,
Formic acid (283
mL, 7.5 mmol, 2.5 equiv) was added to neat
ClSO2NCO (653
m
L, 7.5 mmol, 2.5 equiv) at 0 ꢀC with rapid stirring.
J¼6.9 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
d
82.3, 68.4, 58.5, 34.9,
Vigorous gas evolution was observed during the addition process
and within 5 min the mixture solidified. To the resulting white
mass was added 6.0 mL of CH3CN and the contents were then
warmed to 23 ꢀC. After stirring for 8 h, the mixture was cooled to
0 ꢀC and a solution of alcohol (3.0 mmol) in 5 mL of DMA was added
via cannula. Transfer of the alcohol was made quantitative with an
additional 2ꢃ0.5 mL of DMA. The reaction was warmed to 23 ꢀC
and stirred at this temperature until TLC indicated complete
consumption of starting material (w1 h). The reaction mixture was
quenched by the addition of 20 mL of H2O and poured into a sep-
aratory funnel containing 75 mL of Et2O. The organic phase was
collected and the aqueous layer was extracted with 2ꢃ50 mL of
Et2O. The combined organic extracts were washed with 5ꢃ20 mL of
H2O, dried over MgSO4, and concentrated under reduced pressure.
Purification of the oily residue by chromatography on silica gel
(conditions given below) afforded the desired product.
33.9, 31.6, 29.0, 24.7, 22.5, 14.0 ppm; IR (thin film) n 3283, 3110,
2930, 2860, 1563, 1464, 1366, 1183, 1115, 922, 760 cmꢁ1; HRMS
(ESþ) calcd for C10H23NO4S 253.1348, found 276.1253 (MNaþ).
4.2.1.6. 1-Cyclohexyl-4-methylpentan-2-yl sulfamate (Table 1, entry
6). Purified by chromatography on silica gel (4:1 hexanes/EtOAc);
white solid (90%): TLC Rf¼0.28 (4:1 hexanes/EtOAc); 1H NMR (CDCl3,
400 MHz)
d 4.79–4.72 (m, 1H), 4.69 (br s, 2H), 1.78–1.60 (m, 4H),
1.52–1.40 (m, 2H), 1.31–1.12 (m, 10H), 0.95 (d, 3H, J¼6.4 Hz), 0.93 (d,
3H, J¼6.4 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
d 82.5, 43.8, 42.3,
33.8, 33.4, 33.1, 26.4, 26.1, 26.1, 24.5, 22.7, 22.4 ppm; IR (thin film)
n
3282, 2925, 2852,1561,1449,1360,1182, 921, 761 cmꢁ1; HRMS (ESþ)
calcd for C12H25NO3S 263.1555, found 286.1450 (MNaþ).
4.2.1.7. 2-(Methoxymethyl)-3-methylbutyl sulfamate (Table 1, entry
7). Purified bychromatographyon silica gel(gradientelution: 2:1/
1:1 hexanes/EtOAc); paleyellowoil (73%): TLC Rf¼0.51 (1:1 hexanes/
4.2.1.1. 5-Methyl-1-phenylhexan-3-yl sulfamate (Table 1, entry
1). Purified by chromatography on silica gel (4:1 hexanes/EtOAc);
white solid (70%): TLC Rf¼0.54 (1:1 hexanes/EtOAc); 1H NMR
EtOAc); 1H NMR (CDCl3, 400 MHz)
d 5.27 (br s, 2H), 4.27 (dd, 1H,
J¼9.6, 4.8 Hz), 4.23 (dd, 1H, J¼9.6, 5.4 Hz), 3.45 (dd, 1H, J¼9.6,
4.4 Hz), 3.37 (dd, 1H, J¼9.6, 7.2 Hz), 3.32 (s, 3H), 1.84–1.75 (m, 2H),
0.95 (d, 3H, J¼8.8 Hz), 0.93 (d, 3H, J¼8.8 Hz) ppm; 13C NMR (CDCl3,
(CDCl3, 400 MHz) d 7.32–7.27 (m, 2H), 7.22–7.18 (m, 3H), 4.75–4.68
(m, 1H), 4.68 (br s, 2H), 2.80–2.70 (m, 2H), 2.12–2.00 (m, 2H), 1.81–
1.70 (m, 2H), 1.51 (ddd, 1H, J¼16.0, 9.8, 5.7 Hz), 0.95 (d, 3H,
J¼6.4 Hz), 0.93 (d, 3H, J¼6.4 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
100 MHz) d 70.4, 70.0, 58.7, 44.0, 26.3, 20.0,19.8 ppm; IR (thin film) n
3281, 3107, 2964, 1566, 1467, 1368, 1183, 1113, 931, 832 cmꢁ1; HRMS
(ESþ) calcd for C7H17NO4S 211.0878, found 234.0771 (MNaþ).
d
141.1,128.5,128.4,126.1, 83.8, 43.2, 36.0, 31.0, 24.4, 22.7, 22.4 ppm;
IR (thin film)
n
3285, 2958, 2870, 1558, 1496, 1455, 1358, 1182, 920,
4.2.1.8. 2-Benzyl-3-methoxypropyl sulfamate (Table 1, entry
8). Purified by chromatography on silica gel (gradient elution:
2:1/1:1 hexanes/EtOAc); white solid (75%): TLC Rf¼0.25 (2:1
750 cmꢁ1; HRMS (ESþ) calcd for C13H21NO3S 271.1242, found
294.1138 (MNaþ).
hexanes/EtOAc); mp 51–53 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.32–
4.2.1.2. 1-Methoxy-5-phenylpentan-3-yl sulfamate (Table 1, entry
2). Purified by chromatography on silica gel (2:1 hexanes/EtOAc);
colorless oil (73%): TLC Rf¼0.54 (1:1 hexanes/EtOAc); 1H NMR
7.27 (m, 2H), 7.24–7.16 (m, 3H), 5.01 (br s, 2H), 4.21 (dd, 1H, J¼9.6,
5.2 Hz), 4.17 (dd, 1H, J¼9.6, 5.34 Hz), 3.37 (dd, 1H, J¼9.6, 4.9 Hz),
3.33 (dd, 1H, J¼9.6, 6.6 Hz), 3.32 (s, 3H), 2.72 (dd, 1H, J¼9.6, 5.2 Hz),
2.68 (dd, 1H, J¼9.6, 5.3 Hz), 2.32–2.24 (m, 1H) ppm; 13C NMR
(CDCl3, 400 MHz)
d 7.32–7.27 (m, 2H), 7.22–7.17 (m, 3H), 4.89 (br s,
2H), 4.82–4.75 (m, 1H), 3.59 (ddd, 1H, J¼10.1, 6.8, 5.2 Hz), 3.49 (dt,
(CDCl3, 100 MHz) d 138.8, 129.1, 128.5, 126.4, 71.2, 70.7, 58.8, 40.3,

3048
K.W. Fiori et al. / Tetrahedron 65 (2009) 3042–3051
33.9 ppm; IR (thin film)
n
3367, 3282, 2931, 1560, 1496, 1455, 1368,
the complete consumption of starting material (1–12 h). The re-
action was filtered through a small pad of MgSO4 and the filter cake
rinsed with 2ꢃ2 mL of CH2Cl2. Purification of the isolated material
by chromatography on silica gel (conditions given below) afforded
the desired product.
1183, 1092, 933, 823 cmꢁ1; HRMS (ESþ) calcd for C11H17NO4S
259.0878, found 282.0775 (MNaþ).
4.2.1.9. Pent-4-enyl sulfamate (Table 2, entry 1). Purified by chro-
matography on silica gel (gradient elution: 4:1/2:1 hexanes/
EtOAc); colorless oil (77%): TLC Rf¼0.37 (2:1 hexanes/EtOAc); 1H
4.3.1.1. cis-4-Phenyl-6-(2-methylpropyl)tetrahydro-1,2,3-oxathiazine-
2,2-dioxide (Table 1, entry 1). Purified by chromatography on silica
gel (9:1 hexanes/EtOAc); white solid: TLC Rf¼0.41 (4:1 hexanes/
NMR (CDCl3, 400 MHz) d 5.84–5.74 (m, 1H), 5.10–5.01 (m, 2H), 4.74
(br s, 2H), 4.23 (t, 2H, J¼6.4 Hz), 2.22–2.16 (m, 2H), 1.86 (dq, 2H,
J¼7.9, 6.5 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
d
136.7, 115.9, 70.7,
EtOAc); 1H NMR (CDCl3, 400 MHz)
d 7.43–7.32 (m, 5H), 4.95 (dddd,
29.4, 27.8 ppm; IR (thin film)
n
3381, 3287, 3081, 2978, 1642, 1560,
1H, J¼11.3, 9.1, 4.2, 2.2 Hz), 4.81 (ddd, 1H, J¼12.1, 9.3, 2.8 Hz), 4.22
(br d, 1H, J¼9.1 Hz), 2.04 (dt, 1H, J¼14.3, 2.6 Hz), 1.95–1.85 (m, 1H),
1.88 (dt, 1H, J¼14.3, 11.8 Hz), 1.79 (ddd, 1H, J¼14.3, 8.8, 5.5 Hz), 1.44
(ddd, 1H, J¼14.0, 8.6, 4.2 Hz), 0.97 (d, 3H, J¼6.6 Hz), 0.95 (d, 3H,
1470, 1446, 1366, 1181, 978, 925, 823 cmꢁ1; HRMS (ESþ) calcd for
C5H11NO3S 165.0460, found 188.0355 (MNaþ).
4.2.1.10. (E)-Hex-4-enyl sulfamate (Table 2, entry 2). Purified by
chromatography on silica gel (gradient elution: 4:1/2:1 hexanes/
EtOAc); colorless oil (88%): TLC Rf¼0.32 (2:1 hexanes/EtOAc); 1H
J¼6.7 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
d 138.1, 129.1, 128.9,
126.3, 82.8, 58.3, 44.1, 36.7, 23.8, 22.7, 21.8 ppm; IR (thin film)
n
3266, 2959, 2872, 1498, 1456, 1416, 1362, 1242, 1190, 1075, 1050,
1012, 913, 876, 843, 780 cmꢁ1; HRMS (ESþ) calcd for C13H19NO3S
269.1086, found 292.0983 (MNaþ).
NMR (CDCl3, 400 MHz) d 5.53–5.44 (m, 1H), 5.42–5.34 (m, 1H), 4.69
(br s, 2H), 4.21 (t, 2H, J¼6.4 Hz), 2.14–2.08 (m, 2H),1.80 (dq, 2H, J¼7.6,
6.4 Hz), 1.65 (dq, 3H, J¼6.2, 1.3 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
d
129.1, 126.6, 70.9, 28.5, 28.3, 17.9 ppm; IR (thin film)
n
3378, 3286,
4.3.1.2. trans-4-Phenyl-6-(2-methylpropyl)tetrahydro-1,2,3-oxathia-
2940, 2855,1558,1449,1362, 1180, 1072, 968, 938, 824 cmꢁ1; HRMS
(ESþ) calcd for C6H13NO3S 179.0616, found 202.0513 (MNaþ).
zine-2,2-dioxide (Table 1, entry 1). Clear oil: TLC Rf¼0.34 (4:1
hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d 7.44–7.33 (m, 5H),
4.98–4.88 (m, 2H), 4.44 (br d, 1H, J¼8.4 Hz), 2.39 (ddd, 1H, J¼14.3,
9.1, 5.1 Hz), 2.22 (ddd, 1H, J¼14.3, 9.9, 5.5 Hz), 2.07 (ddd, 1H,
J¼14.5, 5.5, 4.4 Hz), 1.97–1.86 (m, 1H), 1.43 (ddd, 1H, J¼14.2, 8.7,
4.8 Hz), 0.98 (d, 3H, J¼6.6 Hz), 0.97 (d, 3H, J¼6.6 Hz) ppm; 13C
4.2.1.11. (Z)-Hex-4-enyl sulfamate (Table 2, entry 3). Purified by
chromatography on silica gel (2:1 hexanes/EtOAc); colorless oil
(76%): TLC Rf¼0.53 (1:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d
5.57–5.48 (m, 1H), 5.39–5.31 (m, 1H), 4.78 (br s, 2H), 4.22 (t, 2H,
NMR (CDCl3, 100 MHz)
d
138.1, 129.0, 128.5, 126.3, 82.2, 55.3, 42.5,
3266, 2959, 2926, 2872,
J¼6.6 Hz), 2.18 (q, 2H, J¼7.3 Hz), 1.82 (dq, 2H, J¼7.8, 6.6 Hz), 1.62
29.7, 24.3, 22.9, 21.6 ppm; IR (thin film)
n
(ddt, 3H, J¼6.7, 1.8, 0.9 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
d
128.3,
1456, 1417, 1362, 1190, 1089, 1050, 1012, 914, 876, 843, 781 cmꢁ1
;
125.6, 70.9, 28.5, 22.6, 12.8 ppm; IR (thin film)
n
3379, 3286, 3015,
HRMS (ESþ) calcd for C13H19NO3S 269.1086, found 292.0981
(MNaþ).
2942, 1555, 1444, 1365, 1180, 1058, 939, 823 cmꢁ1; HRMS (ESþ)
calcd for C6H13NO3S 179.0616, found 202.0512 (MNaþ).
4.3.1.3. 4,4-Dimethyl-6-(2-phenylethyl)tetrahydro-1,2,3-oxathiazine-
4.2.1.12. Hex-5-enyl sulfamate (Table 2, entry 4). Purified by chro-
matography on silica gel (gradient elution: 4:1/2:1 hexanes/
EtOAc); colorless oil (82%): TLC Rf¼0.35 (2:1 hexanes/EtOAc); 1H
2,2-dioxide (Table 1, entry 1). White solid: TLC Rf¼0.28 (4:1
hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d 7.33–7.28 (m, 2H),
7.24–7.18 (m, 3H), 4.84 (dddd, 1H, J¼8.6, 7.8, 6.0, 4.0 Hz), 4.01 (br
s, 2H), 2.86 (ddd, 1H, J¼13.9, 9.6, 5.0 Hz), 2.75 (ddd, 1H, J¼13.9,
9.2, 7.2 Hz), 2.07 (dddd, 1H, J¼14.2, 9.0, 9.0, 5.2 Hz), 1.88 (dddd,
1H, J¼14.2, 9.6, 7.2, 4.0 Hz), 1.47 (s, 3H), 1.30 (s, 3H) ppm; 13C NMR
NMR (CDCl3, 400 MHz) d 5.84–5.73 (m, 1H), 5.06–4.96 (m, 2H), 4.81
(br s, 2H), 4.22 (t, 2H, J¼6.6 Hz), 2.13–2.06 (m, 2H), 1.80–1.72 (m,
2H), 1.56–1.48 (m, 2H) ppm; 13C NMR (CDCl3, 100 MHz)
d
137.9,
115.2, 71.4, 33.0, 28.1, 24.6 ppm; IR (thin film)
n
3378, 3283, 3078,
(CDCl3, 100 MHz)
d 140.5, 128.6, 128.5, 126.3, 80.2, 55.9, 41.6, 37.1,
2938, 2863, 1640, 1559, 1361, 1179, 917 cmꢁ1; HRMS (ESþ) calcd for
32.0, 30.7, 25.1 ppm; IR (thin film)
n 3267, 3027, 2952, 1496, 1455,
C6H13NO3S 179.0616, found 178.0531 (MþꢁH).
1420, 1389, 1373, 1350, 1192, 1161, 1028, 940, 872, 817 cmꢁ1
;
HRMS (ESþ) calcd for C13H19NO3S 269.1086, found 292.0986
(MNaþ).
4.2.1.13. (ꢂ)-6-Methylhept-1-en-4-yl sulfamate (Fig. 3). Purified by
chromatography on silica gel (4:1 hexanes/EtOAc); colorless oil
(71%): TLC Rf¼0.49 (2:1 hexanes/EtOAc); 1H NMR (CDCl3,
4.3.1.4. cis-4-Phenyl-6-(2-methoxyethyl)tetrahydro-1,2,3-oxathiazine-
2,2-dioxide (Table 1, entry 2). Purified by chromatography on silica
400 MHz)
d
5.87–5.76 (m, 1H), 5.18–5.12 (m, 2H), 4.81 (br s, 2H),
4.71 (dq, 1H, J¼8.4, 5.4 Hz), 2.58–2.44 (m, 2H), 1.82–1.73 (m, 1H),
1.72–1.63 (m, 1H), 1.42 (ddd, 1H, J¼14.3, 8.3, 4.9 Hz), 0.94 (d, 3H,
J¼6.6 Hz), 0.93 (d, 3H, J¼6.6 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
gel (2:1 hexanes/EtOAc); white solid: TLC Rf¼0.56 (1:1 hexanes/
1
EtOAc); H NMR (CDCl3, 400 MHz)
d 7.43–7.33 (m, 5H), 5.06 (dddd,
1H, J¼12.0, 8.0, 4.7, 2.1 Hz), 4.82 (ddd, 1H, J¼12.1, 9.1, 2.8 Hz), 4.15 (br
d
132.7, 118.8, 82.6, 42.9, 39.1, 24.2, 22.9, 22.1 ppm; IR (thin film) n
d, 1H, J¼9.1 Hz), 3.59–3.49 (m, 2H), 3.35 (s, 3H), 2.13 (dt, 1H, J¼14.4,
3370, 3284, 2958, 2927, 2871, 1711, 1561, 1468, 1367, 1183, 920,
773 cmꢁ1; HRMS (ESþ) calcd for C8H17NO3S 207.0929, found
230.0825 (MNaþ).
2.5 Hz), 2.09–1.89 (m, 3H) ppm; 13C NMR (CDCl3, 100 MHz)
d 138.0,
129.2,128.9,126.3, 81.7, 67.4, 58.9, 58.2, 36.3, 35.5 ppm; IR (thin film)
n
3253, 2923, 1497, 1456, 1420, 1363, 1189, 1116, 1065, 1017, 914, 875,
849 cmꢁ1; HRMS (ESþ) calcd for C12H17NO4S 271.0878, found
294.0775 (MNaþ).
4.3. Experimental procedure and characterization data for
C–H insertion products (Tables 1 and 2)
4.3.1.5. cis-4-Phenyl-6-pentyltetrahydro-1,2,3-oxathiazine-2,2-dioxide
(Table 1, entry 3). Purified by chromatography on silica gel (gradient
elution: 9:1/4:1 hexanes/EtOAc); white solid: TLC Rf¼0.44 (4:1
4.3.1. General procedure
To a solution of sulfamate ester (0.25 mmol) in 1.6 mL of CH2Cl2
were added sequentially MgO (23 mg, 0.57 mmol, 2.3 equiv),
PhI(OAc)2 (89 mg, 0.28 mmol, 1.1 equiv), and Rh catalyst (2 mol % of
either Rh2(OAc)4, Rh2(O2CCMe3)4, Rh2(esp)2,12 Rh2(HNCOCF3)4, or
Rh2(O2CCPh3)4, as indicated in Tables 1 and 2). The bright green/
blue suspension was stirred vigorously at 23 ꢀC until TLC indicated
hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d 7.42–7.32 (m, 5H),
4.90–4.82 (m, 1H), 4.81–4.74 (m, 1H), 4.43 (br d, 1H, J¼9.6 Hz), 2.04
(dt, 1H, J¼14.3, 2.6 Hz), 1.92 (dt, 1H, J¼14.3, 11.9 Hz), 1.85–1.75 (m,
1H), 1.71–1.62 (m, 1H), 1.56–1.24 (m, 6H), 0.90 (t, 3H, J¼6.9 Hz) ppm;
13C NMR (CDCl3,100 MHz)
d 138.1,129.0,128.7,126.3, 84.4, 58.3, 36.2,

K.W. Fiori et al. / Tetrahedron 65 (2009) 3042–3051
3049
35.1, 31.2, 24.1, 22.4, 13.9 ppm; IR (thin film)
n
3266, 2956, 2932,
4.3.1.11. trans-4-Phenyl-5-(methoxymethyl)tetrahydro-1,2,3-oxathia-
zine-2,2-dioxide (Table 1, entry 8). Purified by chromatography on
silica gel (4:1 hexanes/EtOAc); white solid: TLC Rf¼0.51 (2:1 hex-
2862, 1499, 1456, 1417, 1363, 1190, 1091, 1055, 1014, 912, 876, 795,
753 cmꢁ1; HRMS (ESþ) calcd for C14H21NO3S 283.1242, found
306.1142 (MNaþ).
anes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d 7.45–7.38 (m, 3H), 7.33–
7.30 (m, 2H), 4.81 (t, 1H, J¼11.7 Hz), 4.70 (dd, 1H, J¼11.2, 8.6 Hz),
4.66 (dd, 1H, J¼11.7, 4.7 Hz), 4.41 (br d, 1H, J¼8.6 Hz), 3.17 (s, 3H),
3.13 (dd, 1H, J¼9.8, 3.1 Hz), 3.01 (dd, 1H, J¼9.8, 6.5 Hz), 2.50–2.40
4.3.1.6. 4-Propyl-6-(2-phenylethyl)tetrahydro-1,2,3-oxathiazine-2,2-
dioxide (Table 1, entry 3). Purified by chromatography on silica gel
(gradient elution: 9:1/4:1 hexanes/EtOAc); colorless oil: TLC
(m, 1H) ppm; 13C NMR (CDCl3, 100 MHz)
d
136.7, 129.4, 129.3, 127.1,
Rf¼0.27 (4:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d
7.33–
74.7, 68.9, 61.1, 59.1, 39.8 ppm; IR (thin film) n 3271, 2926, 1457,
7.27 (m, 2H), 7.24–7.18 (m, 3H), 4.82 (sept, 1H, J¼4.3 Hz), 4.22 (br d,
1H, J¼7.6 Hz), 3.68–3.60 (m, 1H), 2.88 (ddd, 1H, J¼14.0, 9.1, 5.1 Hz),
2.73 (ddd, 1H, J¼14.0, 9.1, 7.4 Hz), 2.36–2.26 (m, 1H), 1.94–1.84 (m,
3H), 1.68 (ddd, 1H, J¼14.4, 5.6, 4.0 Hz), 1.58–1.42 (m, 2H), 1.42–1.31
(m, 1H), 0.93 (t, 3H, J¼7.2 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
1426, 1362, 1190, 1123, 1023, 973, 932, 880, 789 cmꢁ1; HRMS (ESþ)
calcd for C11H15NO4S 257.0722, found 280.0624 (MNaþ).
4.3.1.12. 3-Oxa-2-thia-1-azabicyclo[5.1.0]octane-2,2-dioxide (Table
2, entry 1). Purified by chromatography on silica gel (gradient
elution: 2:1/1:1 hexanes/EtOAc); clear oil: TLC Rf¼0.26 (1:1
d
140.5, 128.6, 128.5, 126.2, 81.6, 53.3, 36.3, 35.3, 33.5, 31.1, 19.3,
13.6 ppm; IR (thin film)
n
3273, 2959, 2933, 2871, 1455, 1420, 1375,
hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d 4.28–4.14 (m, 2H),
1184, 913, 869, 811 cmꢁ1; HRMS (ESþ) calcd for C14H21NO3S
283.1242, found 306.1148 (MNaþ).
2.87–2.81 (m, 1H), 2.72 (d, 1H, J¼5.2 Hz), 2.55–2.46 (m, 1H), 2.53 (d,
1H, J¼5.2 Hz), 2.42–2.31 (m, 1H), 1.99–1.82 (m, 2H) ppm; 13C NMR
(CDCl3, 100 MHz)
d 77.2, 71.3, 39.6, 26.6, 26.2 ppm.
4.3.1.7. 4,4-Dimethyl-6-propyltetrahydro-1,2,3-oxathiazine-2,2-dioxi-
de (Table 1, entry 4). Purified by chromatography on silica gel (6:1
CH2Cl2/hexanes); white solid: TLC Rf¼0.26 (10:1 CH2Cl2/EtOAc); 1H
4.3.1.13. 4-Ethenyltetrahydro-1,2,3-oxathiazine-2,2-dioxide (Table 2,
entry 1). Clear oil: TLC Rf¼0.52 (1:1 hexanes/EtOAc); 1H NMR
NMR (CDCl3, 400 MHz)
d
4.82–4.76 (m, 1H), 4.49 (br s, 1H), 1.75–
(CDCl3, 400 MHz)
d
5.83 (ddd, 1H, J¼17.3, 10.7, 4.9 Hz), 5.32 (dd, 1H,
1.64 (m, 1H), 1.62–1.35 (m, 5H), 1.44 (s, 3H), 1.26 (s, 3H), 0.91 (t, 3H,
J¼17.3, 1.8 Hz), 5.30 (dd, 1H, J¼10.7, 1.7 Hz), 4.81–4.74 (m, 1H), 4.60–
4.55 (m, 1H), 4.40–4.32 (m, 1H), 3.97 (br d, 1H, J¼9.0 Hz), 1.90–1.84
J¼7.3 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
d
81.0, 55.8, 41.4, 37.2,
31.8, 25.1, 17.8, 13.6 ppm; IR (thin film)
n
3266, 2963, 2876, 1466,
(m, 2H) ppm; 13C NMR (CDCl3, 100 MHz)
d 134.9, 117.4, 71.6, 56.8,
1422, 1351, 1193, 1157, 1005, 945, 878, 801 cmꢁ1; HRMS (EI) calcd
for C8H17NSO3 207.0929, found 208.1013 (MHþ).
29.2 ppm; IR (thin film) n 3258, 2962, 2924, 2851, 1421, 1357, 1242,
1186, 1136, 1061, 1015, 988, 936, 864, 783 cmꢁ1; HRMS (ESþ) calcd
for C5H9NO3S 163.0303, found 186.0199 (MNaþ).
4.3.1.8. 4-(2-Methylpropyl)-3-oxa-2-thia-1-azaspiro[5.5]undecane-2,
2-dioxide (Table 1, entry 6). Purified by chromatography on silica gel
(9:1 hexanes/EtOAc); white solid: TLC Rf¼0.64 (2:1 hexanes/EtOAc);
4.3.1.14. trans-8-Methyl-3-oxa-2-thia-1-azabicyclo[5.1.0]octane-2,2-
dioxide (Table 2, entry 2). Purified by chromatography on silica gel
(gradient elution: 2:1/1:1 hexanes/EtOAc); clear oil: TLC Rf¼0.26
1H NMR (CDCl3, 400 MHz)
d
4.91 (dddd, 1H, J¼11.7, 9.0, 4.3, 1.9 Hz),
3.73 (s, 1H), 2.51–2.42 (m, 1H), 1.92–1.82 (m, 1H), 1.77–1.57 (m, 5H),
1.52–1.28 (m, 7H), 1.34 (ddd, 1H, J¼14.2, 8.5, 4.3 Hz), 0.95 (t, 3H,
J¼6.6 Hz), 0.93 (t, 3H, J¼6.6 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
(1:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d 4.27–4.12 (m,
2H), 2.99 (dt, 1H, J¼8.0, 4.0 Hz), 2.62–2.56 (m, 1H), 2.51–2.42 (m,
1H), 2.41–2.30 (m, 1H), 1.98–1.81 (m, 2H), 1.37 (d, 3H,
d
78.7, 57.9, 44.2, 41.6, 40.5, 32.9, 25.6, 23.8, 22.8, 21.9, 21.1,
J¼6.3 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
d 77.2, 71.2, 47.1, 26.9,
20.8 ppm; IR (thin film)
n
3254, 2934, 2864, 1447, 1419, 1386, 1347,
26.4, 17.0 ppm.
1278, 1188, 1158, 1104, 1061, 1028, 994, 974, 939, 877, 791 cmꢁ1
;
HRMS (ESþ) calcd for C12H23NO3S 261.1399, found 284.1304
(MNaþ).
4.3.1.15. 4-((1E)-1-Propenyl)tetrahydro-1,2,3-oxathiazine-2,2-dioxide
(Table 2, entry 2). Clear oil: TLC Rf¼0.32 (2:1 hexanes/EtOAc); 1H
NMR (CDCl3, 400 MHz) d 5.83–5.73 (m, 1H), 5.47–5.39 (m, 1H), 4.75
4.3.1.9. 4,4-Dimethyl-6-(cyclohexylmethyl)tetrahydro-1,2,3-oxathia-
zine-2,2-dioxide (Table 1, entry 6). Purified by chromatography on
silica gel (9:1 hexanes/EtOAc); white solid: TLC Rf¼0.57 (2:1 hex-
(td, 1H, J¼11.7, 3.2 Hz), 4.55 (ddd, 1H, J¼11.7, 4.8, 1.9 Hz), 4.32–4.24
(m, 1H), 3.94 (br d, 1H, J¼9.2 Hz), 1.92–1.86 (m, 2H), 1.73 (dt, 3H,
J¼6.6, 1.4 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
d 129.4, 128.0, 71.6,
56.7, 29.7, 17.8 ppm; IR (thin film) n 3260, 2922, 2853, 1421, 1355,
anes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d
4.93 (dddd, 1H, J¼11.2,
9.0, 4.2, 2.3 Hz), 3.89 (s, 1H), 1.85–1.77 (m, 1H), 1.74–1.63 (m, 5H),
1.62–1.51 (m, 3H), 1.51 (s, 3H), 1.37 (ddd, 1H, J¼14.0, 8.4, 4.1 Hz),
1.29 (s, 3H), 1.29–1.09 (m, 3H), 1.11–0.83 (m, 2H) ppm; 13C NMR
1236, 1186, 1130, 1077, 1049, 1010, 968, 936, 889, 864, 780 cmꢁ1
;
HRMS (ESþ) calcd for C6H11NO3S 177.0460, found 200.0355 (MNaþ).
(CDCl3, 100 MHz)
26.1, 25.9, 25.1 ppm; IR (thin film)
1389, 1373, 1351, 1276, 1192, 1162, 1038, 1012, 944, 871, 801,
787 cmꢁ1; HRMS (ESþ) calcd for C12H23NO3S 261.1399, found
284.1292 (MNaþ).
d
79.1, 55.8, 42.8, 41.9, 33.6, 33.0, 32.5, 31.9, 26.3,
3265, 2925, 2852, 1449, 1422,
4.3.1.16. cis-8-Methyl-3-oxa-2-thia-1-azabicyclo[5.1.0]octane-2,2-di-
oxide (Table 2, entry 3). Purified by chromatography on silica gel
(gradient elution: 9:1/4:1 hexanes/EtOAc); clear oil: TLC Rf¼0.43
n
(2:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d 4.43 (dddd, 1H,
J¼11.9, 5.3, 1.8, 1.0 Hz), 4.30 (td, 1H, J¼11.9, 3.6 Hz), 3.11 (quint, 1H,
J¼6.2 Hz), 2.83 (quint, 1H, J¼5.3 Hz), 2.36–2.20 (m, 2H), 2.15–1.99
(m, 2H), 1.64 (d, 3H, J¼6.4 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
4.3.1.10. 4,4-Dimethyl-5-(methoxymethyl)tetrahydro-1,2,3-oxathia-
zine-2,2-dioxide (Table 1, entry 7). Purified by chromatography on
silica gel (gradient elution: 3:1/2:1 hexanes/EtOAc); clear oil: TLC
d
77.2, 71.9, 44.5, 26.0, 22.2, 9.2 ppm; IR (thin film) n 2972, 2932,
1439, 1363, 1290, 1259, 1180, 1114, 1062, 1006, 983, 966, 916, 889,
847, 825, 761 cmꢁ1
Rf¼0.47 (1:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
d
4.69 (dd,
.
1H, J¼12.0, 4.0 Hz), 4.60 (dd,1H, J¼12.0, 8.7 Hz), 4.25 (br s, 1H), 3.48
(dd, 1H, J¼9.6, 4.3 Hz), 3.34 (s, 3H), 3.27 (dd, 1H, J¼9.6, 8.4 Hz),
2.03–1.96 (m, 1H), 1.41 (s, 3H), 1.35 (s, 3H) ppm; 13C NMR (CDCl3,
4.3.1.17. 4-((1Z)-1-Propenyl)tetrahydro-1,2,3-oxathiazine-2,2-dioxide
(Table 2, entry 3). Clear oil: TLC Rf¼0.75 (2:1 hexanes/EtOAc); 1H
100 MHz)
film)
d
71.2, 69.6, 59.2, 58.1, 42.6, 29.7, 29.4, 23.0 ppm; IR (thin
NMR (CDCl3, 400 MHz)
d
5.75 (dddd, 1H, J¼14.0, 10.7, 7.0, 1.2 Hz),
n
3270, 2922, 2851, 1465, 1426, 1391, 1357, 1225, 1185, 1162,
5.24 (dddd, 1H, J¼10.7, 8.0, 3.8, 1.8 Hz), 4.79 (ddd, 1H, J¼12.8, 11.7,
2.5 Hz), 4.65–4.56 (m,1H), 4.56 (ddd,1H, J¼11.7, 4.9,1.5 Hz), 3.90 (br
s, 1H), 1.93–1.81 (m, 1H), 1.75 (dt, 3H, J¼7.0, 1.8 Hz), 1.75–1.69 (m,
1112, 990, 928, 895, 794 cmꢁ1; HRMS (ESþ) calcd for C7H15NO4S
209.0722, found 232.0623 (MNaþ).

3050
K.W. Fiori et al. / Tetrahedron 65 (2009) 3042–3051
1H) ppm; 13C NMR (CDCl3, 100 MHz)
d
130.7, 126.9, 71.8, 52.6, 29.9,
tetracarboxylates were desolvated immediately prior to use by
heating solid samples to 90 ꢀC under reduced pressures (w1 Torr)
for 2 h. Sulfamate substrates were dried azeotropically with ben-
zene and stored under vacuum. Product conversion was de-
termined by integration of the 1H NMR spectra. Maximum product
concentration was fixed at 0.157 M (¼initial concentration of sul-
famate ester). Standard reactant concentrations were chosen to
match those used in the general protocol for the preparation of
oxathiazinanes (vide supra):
13.6 ppm; IR (thin film) n 3242, 3027, 2980, 2923, 1432, 1349, 1239,
1187, 1171, 1090, 1061, 1026, 998, 944, 907, 866, 784 cmꢁ1; HRMS
(ESþ) calcd for C6H11NO3S 177.0460, found 200.0358 (MNaþ).
4.3.1.18. 3-Oxa-2-thia-1-azabicyclo[6.1.0]nonane-2,2-dioxide (Table
2, entry 4). Purified by chromatography on silica gel (2:1 hexanes/
EtOAc); clear oil: TLC Rf¼0.37 (2:1 hexanes/EtOAc); 1H NMR (CDCl3,
400 MHz)
d
4.60 (ddd, 1H, J¼12.8, 7.0, 3.0 Hz), 4.36 (ddd, 1H, J¼12.8,
7.6, 3.4 Hz), 2.77 (d, 1H, J¼6.7 Hz), 2.77–2.65 (m, 1H), 2.42 (d, 1H,
J¼4.9 Hz), 2.24–2.04 (m, 3H), 2.03–1.93 (m, 1H), 1.80–1.68 (m, 1H),
[sulfamate ester]¼0.157 M in CH2Cl2 or CD2Cl2
[Rh2(O2CCMe3)4]¼3.14 mM in CH2Cl2 or CD2Cl2 (0.02ꢃsulfamate
ester concentration)
1.38–1.25 (m, 1H) ppm; 13C NMR (CDCl3, 100 MHz)
d 74.9, 42.4, 35.7,
28.9, 27.7, 25.6 ppm; IR (thin film)
n 3308, 2936, 2865, 1439, 1353,
1248, 1176, 1085, 1022, 968, 925, 865, 817 cmꢁ1; HRMS (ESþ) calcd
[PhI(OAc)2]¼0.173 M in CH2Cl2 or CD2Cl2 (1.1ꢃsulfamate ester
for C6H11NO3S 177.0460, found 176.0372 (MþꢁH).
concentration)
4.3.1.19. 4,4-Dimethyl-6-(2-propen-1-yl)tetrahydro-1,2,3-oxathiazine-
2,2-dioxide. Purified by chromatography on silica gel (gradient elu-
tion: 3:1/1: hexanes/EtOAc); clear oil: TLC Rf¼0.51 (2:1 hexanes/
4.4.2. 1H NMR method for determining product conversions
Magnesium oxide was omitted from these experiments. To de-
termine the rates of product formation at the standard reactant
EtOAc); 1H NMR (CDCl3, 400 MHz)
d 5.83–5.73 (m,1H), 5.20–5.14 (m,
2H), 4.86 (ddd, 1H, J¼11.4, 6.2, 2.4 Hz), 4.19 (br s, 1H), 2.56–2.48 (m,
1H), 2.44–2.36 (m, 1H), 1.66 (dd, 1H, J¼14.3, 2.4 Hz), 1.58 (dd, 1H,
J¼14.3, 11.5 Hz), 1.49 (s, 3H), 1.30 (s, 3H) ppm; 13C NMR (CDCl3,
concentrations,
a CD2Cl2 solution of isoamyl sulfamate and
Rh2(O2CtBu)4 (0.314 M and 6.28 mM, respectively) and a CD2Cl2
solution of PhI(OAc)2 (0.346 M) were prepared; 300 mL of each so-
100 MHz)
film)
d
131.4, 119.3, 80.0, 55.8, 40.7, 39.4, 31.8, 25.1 ppm; IR (thin
lution was co-injected into a Pyrex NMR tube at 23 ꢀC and the 1H
NMR spectrum was immediately acquired. The NMR probe tem-
perature was maintained at 22.6 ꢀC. Reaction progress was moni-
tored by periodic 1H NMR acquisition.
n
3268, 2979, 2926, 1423,1390,1374,1351, 1192, 1157, 1015, 944,
925, 888, 871, 815, 785 cmꢁ1; HRMS (ESþ) calcd for C8H15NO3S
205.0773, found 228.0676 (MNaþ).
4.3.2. Characterization data for cyclopropyl clock experiment
(Fig. 6)
4.4.3. Sample analysis method for determining product conversion
The use of MgO was compatible with kinetic analysis performed
under these conditions; however, in order to have a direct com-
parison to results from the 1H NMR experiments, MgO was typically
4.3.2.1. (ꢂ)-3-(trans-2-Phenylcyclopropyl)propyl sulfamate. Purified
by chromatography on silica gel (3:1 hexanes/EtOAc); white solid
(69%): TLC Rf¼0.21 (3:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
omitted. Aliquots (100 mL) were removed periodically from the
reaction mixture and injected into a rapidly stirring mixture of
1.0 mL of 1.0 M aqueous Na2S2O3 and 1.0 mL of CH3CN. EtOAc was
added (5 mL) and the organic portion was collected and concen-
trated under reduced pressure. The isolated material was dissolved
in CDCl3 and the product ratio was determined by integration of the
1H NMR spectrum or by integration of the HPLC chromatogram.
d
7.27–7.23 (m, 2H), 7.14 (tt, 1H, J¼7.6, 1.2 Hz), 7.05–7.03 (m, 2H),
4.76 (br s, 2H), 4.26 (t, 2H, J¼6.4 Hz), 1.94–1.87 (m, 2H), 1.68–1.63
(m, 1H), 1.61–1.44 (m, 2H), 1.07–0.99 (m, 1H), 0.93 (dt, 1H, J¼8.4,
5.2 Hz), 0.79 (dt, 1H, J¼8.4, 5.2 Hz) ppm; 13C (CDCl3, 100 MHz)
d
143.4, 128.3, 125.5, 125.4, 71.1, 30.2, 28.6, 23.2, 22.8, 16.1 ppm; IR
(thin film)
n 3387, 3288, 2926,1604,1556, 1497, 1365,1182, 937, 822,
751, 699 cmꢁ1
.
4.4.4. Pseudo-first-order kinetics experiments to determine the rate
dependence on [PhI(OAc)2]
4.3.2.2. (ꢂ)-4-(trans-2-Phenylcyclopropyl)tetrahydro-1,2,3-oxathia-
zine-2,2-dioxide. Reaction performed with 5 mol % Rh2(OAc)2.
Purified by chromatography on silica gel (15:1 CH2Cl2/EtOAc);
white solid (91%, 1:1 mixture of diastereomers by 1H NMR). A
single diastereomer of the product (stereochemistry unassigned)
could be obtained by recrystallization from hexanes/EtOAc: TLC
Product concentration was determined by analyzing sample
aliquots taken at intermediate time points. Reactant concentrations
were taken as follows and correspond to the reactant concentra-
tions and equivalencies employed in the general protocol for the
preparation of oxathiazinanes except the sulfamate concentration
is 10 times that of a standard reaction (9 equiv compared to oxi-
dant) (vide supra):
Rf¼0.41 (CH2Cl2); 1H NMR (CDCl3, 400 MHz)
d 7.32–7.28 (m, 2H),
7.24–7.21 (m, 2H), 7.10–7.07 (m, 2H), 4.76–4.71 (m, 1H), 4.58 (dt,
1H, J¼8.8, 2.8 Hz), 4.24 (d, 1H, J¼7.6 Hz), 3.34–3.28 (m, 1H), 1.98–
1.93 (m, 2H), 1.25–1.20 (m, 1H), 1.15 (dt, 1H, J¼7.2, 4.4 Hz), 1.09 (dt,
[sulfamate ester]¼1.57 M in CH2Cl2 (9.0ꢃPhI(OAc)2 concentration)
[Rh2(O2CCMe3)4]¼7.85 mM in CH2Cl2 (0.045ꢃPhI(OAc)2 concentration)
[PhI(OAc)2]¼0.173 M in CH2Cl2
1H, J¼6.8, 4.4 Hz) ppm; 13C NMR (CDCl3, 100 MHz)
d 140.9, 128.5,
126.2, 125.9, 71.7, 60.0, 29.8, 26.6, 21.9, 13.7 ppm; IR (thin film)
n
3267, 1420, 1357, 1187, 1062, 1014, 941, 910, 861, 778 cmꢁ1
.
Acknowledgements
4.4. Kinetic experiments
We would like to thank the many authors who have contributed
to this commemorative issue and the awards committee for their
gracious acknowledgement of our work. We are indebted to our
colleague, John Brauman, for many stimulating discussions and his
insightful analysis and to a reviewer for a deep and scholarly
analysis of our submitted draft. K.W.F. is grateful to both the Na-
tional Science Foundation and Amgen for fellowship support. C.G.E.
is grateful to both the National Science Foundation and the Amer-
ican Chemical Society Organic Division for fellowship support.
B.H.B. was the recipient of an Eli Lilly graduate fellowship award.
4.4.1. General procedure
Reactions were conducted in anhydrous CH2Cl2 distilled from
CaH2 and stored over activated 4 Å molecular sieves or dried by
passage through activated alumina columns under 12 psi of N2.
Standard solutions of reagents in CH2Cl2 were stored in Schlenk
flasks at ꢁ20 ꢀC to minimize solvent evaporation. PhI(OAc)2 was
obtained from Acros Chemical Company and all experiments
employed oxidant from the same lot number. Dimeric Rh-

K.W. Fiori et al. / Tetrahedron 65 (2009) 3042–3051
3051
17. In some cases, Rh2(O2CCPh3)4 has been found to influence adversely diaster-
eoselective sulfamate ester insertions. For examples of diastereoselective
sulfamate oxidation reactions, see: Wehn, P. M.; Lee, J.; Du Bois, J. Org. Lett.
2003, 5, 4823–4826.
The National Science Foundation, the National Institutes of Health,
Amgen, Boehringer-Ingelheim, GlaxoSmithKline, Merck, and Pfizer
are acknowledged for their generous support of this work.
18. For Rh-catalyzed alkene aziridination, see: (a) Mu¨ller, P.; Baud, C.; Jacquier, Y.
Can. J. Chem. 1998, 76, 738–750; (b) Fruit, C.; Robert-Peillard, F.; Bernardinelli,
G.; Mu¨ller, P.; Dauban, P.; Dodd, R. H. Tetrahedron: Asymmetry 2005, 16, 3484–
3487; (c) Bodner, R.; Marcellino, B. K.; Severino, A.; Smenton, A. L.; Rojas, C. M.
J. Org. Chem. 2005, 70, 3988–3996; (d) Guthikonda, K.; Wehn, P. M.; Caliando, B.
J.; Du Bois, J. Tetrahedron 2006, 62, 11331–11342 and Ref. 2f.
19. For examples of catalysts that strongly favor allylic C–H insertion, see: (a) Za-
latan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 9220–9221; (b) Milczek, E.;
Boudet, N.; Blakey, S. Angew. Chem., Int. Ed. 2008, 47, 6825–6828.
20. A related bicyclic structure has been prepared previously, see: Wehn, P. M.; Du
Bois, J. Org. Lett. 2005, 7, 4685–4688 and Ref. 2c.
References and notes
1. For reviews on C–H amination, see: (a) Espino, C. G.; Du Bois, J. In Modern
Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim,
2005; pp 379–416; (b) Dauban, P.; Dodd, R. H. Synlett 2003, 1571–1586; (c)
Mu¨ller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905–2920; (d) Halfen, J. A. Curr. Org.
Chem. 2005, 9, 657–669; (e) Lebel, H.; Leogane, O.; Huard, K.; Lectard, S. Pure
Appl. Chem. 2006, 78, 363–375; (f) Li, Z. G.; He, C. Eur. J. Org. Chem. 2006, 4313–
4322; (g) Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45, 6422–6425; (h) Davies,
H. M. L.; Manning, J. R. Nature 2008, 451, 417–424; (i) Dı´az-Requejo, M. M.;
21. A similar strategy was used to perform a Hammett analysis of Rh-catalyzed
carbene C–H insertion, see: Wang, J.; Chen, B.; Bao, J. J. Org. Chem. 1998, 63,
1853–1862.
´
Perez, P. J. Chem. Rev. 2008, 108, 3379–3394.
22. We have found that Rh2(OAc)4 and Rh2(oct)4 may be used interchangeably with
no consequence to product yields or selectivities.
2. Recent, representative examples include: (a) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.;
Yu, W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465–3468; (b) Fiori, K. W.;
Fleming, J. J.; Du Bois, J. Angew. Chem., Int. Ed. 2004, 43, 4349–4352; (c) Fruit, C.;
Mu¨ller, P. Tetrahedron: Asymmetry 2004, 15, 1019–1026; (d) Cui, Y.; He, C. Angew.
Chem., Int. Ed. 2004, 43, 4210–4212; (e) Espino, C. G.; Fiori, K. W.; Kim, M.; Du
Bois, J. J. Am. Chem. Soc. 2004, 126, 15378–15379; (f) Lebel, H.; Huard, K.; Lectard,
S. J. Am. Chem. Soc. 2005, 127, 14198–14199; (g) Kim, M.; Mulcahy, J. V.; Espino, C.
G.; Du Bois, J. Org. Lett. 2006, 8, 1073–1076.
3. For some examples of C–H amination in natural product synthesis, see: (a) Wehn,
P. M.; Du Bois, J. J. Am. Chem. Soc. 2002,124,12950–12951; (b) Trost, B. M.; Gunzner,
J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 10396–10415; (c) Huang, H.;
Panek, J. S. Org. Lett. 2003, 5, 1991–1993; (d) Parker, K. A.; Chang, W. S. Org. Lett.
2003, 5, 3891–3893; (e) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510–
11511; (f) Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926–3927.
4. Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 562–568.
5. For related mechanistic studies, see: (a) Na¨geli, I.; Baud, C.; Bernardinelli, G.;
Jacquier, Y.; Moran, M.; Mu¨ ller, P. Helv. Chim. Acta 1997, 80, 1087–1105; (b)
Mu¨ller, P.; Baud, C.; Na¨geli, I. J. Phys. Org. Chem. 1998, 11, 597–601; (c) Au, S.-M.;
Huang, J.-S.; Yu, W.-Y.; Fung, W.-H.; Che, C.-M. J. Am. Chem. Soc. 1999, 121, 9120–
9132; (d) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Che, C.-M. J. Org. Chem. 2004, 69,
3610–3619; (e) Leung, S. K.-Y.; Tsui, W.-M.; Huang, J.-S.; Che, C.-M.; Liang, J.-L.;
Zhu, N. J. Am. Chem. Soc. 2005, 127, 11629–16640; (f) Badiei, Y. M.; Krish-
naswamy, A.; Melzer, M. M.; Warren, T. H. J. Am. Chem. Soc. 2006, 128, 15056–
15057; (g) Huard, K.; Lebel, H. Chem.dEur. J. 2008, 14, 6222–6230.
23. This
r
-value was obtained by plotting log(kAr/kPh) versus sþ (R2¼0.9575).
Plotting this data versus sp gives an R2 of 0.9113.
24. (a) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry,
3rd ed.; Harper & Row: New York, NY, 1987; pp 143–154; (b) Hansch, C.; Leo, A.;
Taft, R. W. Chem. Rev. 1991, 91, 165–195.
25. Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem. 2002, 67, 4165–
4169.
26. The 13C NMR spectrum was acquired using a relaxation delay of 5 s. This
method for determining the ratio of isotopomers has been utilized by Wang
and Adams, see Ref. 27a.
27. (a) Wang, P.; Adams, J. J. Am. Chem. Soc. 1994, 116, 3296–3305; (b) Davies, H. M.
L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063–3070.
28. Lwowski, W.; Maricich, T. J. J. Am. Chem. Soc. 1965, 87, 3630–3637.
29. Au, S.-M.; Huang, J.-S.; Che, C.-M.; Yu, W.-Y. J. Org. Chem. 2000, 65, 7858–7864.
30. Lin, X.; Zhao, C.; Che, C.-M.; Ke, Z.; Phillips, D. L. Chem. Asian J. 2007, 2,
1101–1108; Also, see: Lin, X.; Che, C.-M.; Phillips, D. L. J. Org. Chem. 2008, 73,
529–537.
31. (a) Lwowski, W. In Nitrenes; Lwowski, W., Ed.; Interscience: New York, NY, 1970;
pp 185–224; (b) Terashima, S.; Yamada, S.-i. Chem. Pharm. Bull. 1968, 16, 1953–
1971; Also, see: Liu, J.; Mandel, S.; Hadad, C. M.; Platz, M. S. J. Org. Chem. 2004,
69, 8583–8593.
32. For a recent analysis of Cu(I)-promoted C–H amination, see: Badiei, Y. M.;
Dinescu, A.; Dai, X.; Palomino, R. M.; Heinemann, F. W.; Cundari, T. R.; Warren,
T. H. Angew. Chem., Int. Ed. 2008, 47, 9961–9964 and references therein.
33. Mu¨ller has performed an analogous intermolecular amination reaction using
NsN]IPh, catalytic Rh2(OAc)4, and a cyclopropane clock that ring-opens with
a rate constant of 2ꢃ1010 sꢁ1, see Ref. 5a.
6. Du Bois, J. CHEMTRACTSdOrg. Chem. 2005, 18, 1–13.
7. Impressive examples of Rh-catalyzed intermolecular C–H amination have also
appeared, see Ref. 4: (a) Liang, C.; Robert-Peillard, F.; Fruit, C.; Mu¨ller, P.; Dodd, R. H.;
Dauban, P. Angew. Chem., Int. Ed. 2006, 45, 4641–4644;(b)Liang, C.; Fruit, C.; Robert-
Peillard, F.; Mu¨ller, P.; Dodd, R. H.; Dauban, P. J. Am. Chem. Soc. 2008, 130, 343–350.
8. Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598–600.
9. For general reviews, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methodsfor Organic SynthesiswithDiazo Compounds: From Cyclopropanes to Ylides;
Wiley and Sons: New York, NY,1997; (b) Davies, H. M. L.; Beckwith, E. J. Chem. Rev.
2003, 103, 2861–2904; (c) Doyle, M. P. J. Org. Chem. 2006, 71, 9253–9260.
10. (a) Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181–
7192; (b) Nowlan, D. T., III; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A. J. Am.
Chem. Soc. 2003, 125, 15902–15911; (c) Wong, F. M.; Wang, J.; Hengge, A. C.; Wu,
W. Org. Lett. 2007, 9, 1663–1665.
34. Simakov, P. A.; Choi, S.-Y.; Newcomb, M. Tetrahedron Lett. 1998, 39, 8187–8190.
35. Choi, S.-Y.; Toy, P. H.; Newcomb, M. J. Org. Chem. 1998, 63, 8609–8613.
36. It is difficult to establish the precise role for MgO in the amination reaction due
to its insolubility in CH2Cl2 and C6H6. In its presence, we have observed
a diminution in the initial rate of product formation (as determined by HPLC
analysis of reaction aliquots). In its absence, we have noted that PhI(OAc)2 is
consumed more rapidly than oxathiazinane product is formed.
37. We have attempted to lower the catalyst loadings below 0.1 mol % in order to
observe a rate influence on catalyst concentration. At such low catalyst load-
ings, the product is not formed at appreciable levels.
11. For general discussions on mechanisms of C–H oxidation, see: (a) Newcomb,
M.; Toy, P. H. Acc. Chem. Res. 2000, 33, 449–455; (b) Groves, J. T. J. Inorg. Biochem.
2006, 100, 434–447.
38. Under standard conditions the substrate concentration is 0.157 M.
39. Iminoiodinane 15 was employed for these studies as it is more easily prepared
and isolated than iminoiodinanes derived from other sulfamate starting
materials.
12. Rh2(esp)2¼Rh2(
a,a, ,a
a0 0-tetramethyl-1,3-benzenedipropionate)2, see Ref. 2e.
This catalyst may be purchased from Aldrich Chemical Company.
13. Rh2(O2CCPh3)4 was first described by Ikegami, see: Hashimoto, S.-i.; Watanabe,
N.; Ikegami, S. Tetrahedron Lett. 1992, 33, 2709–2712.
40. 1H NMR experiments with PhI(OAc)2 and carbamate esters also show no
apparent reaction between these starting materials.
41. A control experiment with PhI(OAc)2 and 1,1,1-trichloro-4-phenylbutan-2-yl
sulfamate shows w10% of the corresponding iminoiodinane. A similar obser-
vation has been noted with 2,2,2-trichloroethylsulfamate, see Ref. 4.
42. Intermolecular C–H amination experiments involving the kinetic resolution of
chiral sulfonimidamides support the idea of reversible iodoimine formation,
see Ref. 7b.
14. For a leading reference on selectivity influences caused by ligands on dirho-
dium(II) complexes, see: Doyle, M. P.; Ren, T. Prog. Inorg. Chem. 2001, 49, 113–168.
15. Related observations have been noted by Che in reactions catalyzed by Ru–
porphyrin complexes, see Ref. 5c.
16. An increased preference for 3ꢀ over benzylic C–H insertion was noted in di-
azoalkane reactions promoted by Rh2(O2CCPh3)4, see: Taber, D. F.; Joshi, P. V.
J. Org. Chem. 2004, 69, 4276–4278.
43. Espino, C. G. Ph.D. Thesis, Stanford University, Stanford, CA, 2004.