Rhodium-Catalyzed Regiodivergent Hydrothiolation of Allyl Amines and Imines

Article abstract of DOI:10.1021/jacs.6b07142

The regiodivergent Rh-catalyzed hydrothiolation of allyl amines and imines is presented. Bidentate phosphine ligands with larger natural bite angles (β_n ≥ 99°), for example, DPEphos, dpph, or L1, promote a Markovnikov-selective hydrothiolation in up to 88% yield and >20:1 regioselectivity. Conversely, when smaller bite angle ligands (β_n ≤ 86°), for example, dppbz or dppp, are employed, the anti-Markovnikov product is formed in up to 74% yield and >20:1 regioselectivity. Initial mechanistic investigations are performed and are consistent with an oxidative addition/olefin insertion/reductive elimination mechanism for each regioisomeric pathway. We hypothesize that the change in regioselectivity is an effect of diverging coordination spheres to favor either Rh-S or Rh-H insertion to form the branched or linear isomer, respectively.

Full text of DOI:10.1021/jacs.6b07142

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Article
Rhodium-Catalyzed Regiodivergent
Hydrothiolation of Allyl Amines and Imines
Jennifer L Kennemur, Gregory D Kortman, and Kami L. Hull
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07142 • Publication Date (Web): 22 Aug 2016
Downloaded from http://pubs.acs.org on August 22, 2016
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Journal of the American Chemical Society
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Rhodium-Catalyzed Regiodivergent Hydrothiolation of Allyl
Amines and Imines
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Jennifer L. Kennemur, Gregory D. Kortman, and Kami L. Hull*
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews, Urbana, IL 61801.
Supporting Information Placeholder
ABSTRACT: The regiodivergent Rh-catalyzed hydrothiolation of allyl amines and imines is presented. Bidentate phosphine ligands with larger
natural bite angles (bn ≥ 99°), e.g., DPEphos, dpph, or L1, promote a Markovnikov-selective hydrothiolation in up to 88% yield and >20:1
regioselectivity. Conversely, when smaller bite angle ligands
(bn ≤ 86°), e.g., dppbz or dppp, are employed, the anti-Mar-
kovnikov product is formed in up to 74% yield and >20:1 re-
gioselectivity. Initial mechanistic investigations are per-
formed and are consistent with an oxidative addition/olefin
insertion/reductive elimination mechanism for each regioi-
someric pathway. We hypothesize that the change in regiose-
lectivity is an effect of diverging coordination spheres to favor
either Rh–S or Rh–H insertion to form the branched or lin-
ear isomer, respectively.
H
SR3
Catalyst-Controlled,
Regiodivergent Hydrothiolation
R12N
R12N
SR3
H
R2
R2
R3S–H
23 examples
up to 88% yield
up to >20:1 dr
8 examples
up to 74% yield
+
[(P~P)RhCl]2
βn ≥ 99°
[(P~P)RhCl]2
βn ≤ 86°
R12N
R2
INTRODUCTION
Scheme 1. Hydrothiolation of unsaturated C–C bonds
Hydrothiolation reactions directly couple two abundant building
blocks, i.e., a thiol and an unsaturated C–C bond, to form a C–S and
C–H bond with 100% atom economy.1 This efficient strategy to-
ward C–S bonds is highly valuable, as organosulfur compounds are
common synthetic intermediates2 and composed approximately
20% of the top-selling US pharmaceutical drugs in 2012.3 Compared
to other hydrofunctionalization methods, however, transition metal-
catalyzed hydrothiolation is relatively underexplored, likely due to
sulfur’s strong coordinating ability and ensuing catalyst deactiva-
tion.4
Previous work:
(a) Hydrothiolation of alkynes
R2
H
R2
R1S
R2
cat. [M]
cat. [M]
+
H
H
SR1
R1SH
(b) Hydrothiolation of allenes
cat. [M]
R2
R3
R1S
R2
R3
*
R1SH
[M]
R2 R3
Since the first transition metal-catalyzed hydrothiolation break-
through by Ogawa in 1992,5 organometallic chemists have designed
catalytic systems capable of selectively synthesizing both linear and
branched C–S bonds from alkynes and allenes (Scheme 1a-b).6,7 In
contrast, transition metal-catalyzed hydrothiolations of alkenes is
relatively underdeveloped. 8 Ogawa recently demonstrated the Au-
catalyzed anti-Markovnikov hydrothiolation of terminal olefins to
afford linear C–S bonds.9 However, thus far, only electronically acti-
vated alkenes have afforded branched C–S bonds (Scheme 1c).10
(c) Hydrothiolation of alkenes
SR1
H
cat. [M]
R1SH
+
AG
AG
AG = Ph, vinyl, OR, NC(O)
This work:
(d) Regiodivergent hydrothiolation of alkenes
R1SH
H
SR1
cat. [Rh]
cat. [Rh]
R3R2N
R3R2N
+
SR1
H
R4
R4
R3R2N
The development of alkene functionalizations is an important
challenge in modern catalysis.11 Our group is specifically interested
in using transition metal-catalysis to form C–X bonds from these
ubiquitous organic moieties with high degrees of regio-, chemo-, and
stereoselectivity.
R4
Markovnikov Selective
Conditions
anti-Markovnikov Selective
Condtions
Lewis basic nitrogen binds to the catalyst and promotes the func-
tionalization of the proximal alkene.13 The regioselectivity is dictated
by the formation of the favored, five-membered metallacyclic inter-
mediate.
Recently, we demonstrated the Rh-catalyzed hydroamination of
allylimines and homoallylamines for the selective synthesis of 1,2-
diamines and 1,4-diamines, respectively.12 We propose that the
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Page 2 of 6
Figure 1. Relevant compounds containing a 1,2-aminothioether
functionality
Table 1. Effect of bidentate phosphine ligand on the Rh-catalyzed
hydrothiolation reaction.
1
2
3
4
5
6
7
8
(a) 1,2-N,S moiety found in modern pharmaceuticals14
:
MeO
H
H
N
1.5 equiv. PhSH
O
SPh
1 mol % [Rh(cod)Cl]2
2.5 mol % ligand
H
H
O
3a
MeO
N
H
H
+
H
N
O
NH
O
H
HO
N
O
N
toluene, 100 °C, 6 h
S
S
NH
MeO
SPh
H
O
O
2a
H
N
NH
O
N
S
S
O
O
1.0 equiv
HN
NH
OH
9
O
3aʹ
OH
10
11
12
13
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16
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22
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60
Penicillin G
Viracept
Istodax
a
bn
3ab
3a¢b
entry
ligand
dppbz
dppe
yield
yield
3%
(b) 1,2-N,S ligands used for Pd-catalyzed allylic substitution:15
1
2
3
4
5
6
7
8
83°
85°
86°
99°
<1%
<1%
<1%
12%
31%
32%
66%
21%
NMe2
S
O
N
Me
Ph
MeS
tBu
tBuS
7%
Ph
Fe
N
SPh
N
Ar
dppp
19%
<1%
<1%
<1%
<1%
<1%
Ph
We hypothesized that a similar approach may allow for the Mar-
kovnikov-selective hydrothiolation of electronically unactivated al-
lyl amines and imines to afford 1,2-amino- and iminothioethers, re-
spectively. The 1,2-N,S- moiety is commonly found in modern phar-
maceuticals14 (Figure 1, (a)) and as bidentate ligands for palladium-
catalyzed allylic substitution reactions15,16 (Figure 1, (b)). However,
thus far, the incorporation of these moieties has, in many cases, de-
pended on pre-installed functionality from ephedrine and cysteine,
limiting substitution patterns for derivatization along the carbon
skeleton. The development of a more general methodology for the
synthesis of 1,2-aminothioethers may enable broader applicability of
this moiety with increased structural diversity.
dppb
dpppent
dpph
DPEphos
L1
102°
168°
Ph2P
PPh2
n
O
O
n=0, dppe
n=1, dppp
Ph2P
PPh2
Ph2P
PPh2 P(NEt2)2 P(NEt2)2
dppbz
n=2, dppb
n=3, dpppent
n=4, dpph
DPEphos
L1
Herein we disclose an efficient synthesis of 1,2-aminothioethers
via the hydrothiolation of easily accessible allyl amine derivatives. To
our surprise, the regioselectivity of the olefin functionalization is lig-
and-controlled, allowing us to access both 1,2- and 1,3-aminothi-
oethers from a common starting material (Scheme 1d).
a Natural bite angle (bn), as defined by the preferred chelation angle
based on the ligand backbone and not on the metal valence angle.18
b
Yield determined by comparison to an internal standard using gas chro-
matography.
suggesting a change in mechanism, based on the ligand employed,
that allows for a catalyst-controlled, regiodivergent hydrothiolation
reaction.
RESULTS AND DISCUSSION
Our initial attempt at the Rh-catalyzed hydrothiolation of alkenes
explored the use of thiophenol under our previously optimized con-
ditions for the hydroamination reaction. Excitingly, we found that
allyl imine 1a and secondary allyl amine 2a act as directing groups,
affording the Markovnikov-selective hydrothiolation product, albeit
in trace quantities, as detected by GC analysis (Eq. 1).17
Next, our efforts focused on exploring the scope of the Markovni-
kov-selective hydrothiolation reaction. We found that increasing
catalyst loading, thiol equivalents, and time led to a more general re-
action scope. 17 The addition of 0.5 equivalents of LiBr increases the
yield, potentially a consequence of suppressed product inhibition or
an effect of a more active rhodium-bromide intermediate following
salt metathesis.
3 equiv. PhSH
0.5 mol% [Rh(cod)Cl]2
1 mol % AgBF4
MeO
H
MeO
1 mol % DPEphos
H
(1)
H
As demonstrated in Table 2, secondary amines and imines are ex-
cellent directing groups for hydrothiolation, affording 1,2-aminothi-
oethers in good yields (38-82%) with excellent regioselectivity
(>20:1 in all cases). Notably, the ligand employed is dependent on
the substrate, i.e., with imines, higher yields are observed with L1
(Table S8); whereas DPEphos affords higher yields when starting
with a secondary amine (Table 1). The imine products are not stable
to column chromatography; thus, these compounds are isolated by
immediate reduction to the corresponding 1,2-aminothioether.
These products can also be accessed through a three-component
procedure, i.e. starting with p-methoxybenzaldehyde and allyl
amine, a one-pot imine condensation and in-situ hydrothiolation re-
action with thiophenol yielded 3a in 58% isolated yield following
reduction with NaBH4.17
N
MeCN, 60 °C, 24 h
N
SPh
2a
3a
Observed in <5% in situ yield
Increasing catalyst loading and temperature along with using a
non-polar solvent, led to the formation of 3a in 66% yield from amine
2a with >20:1 selectivity for the Markovnikov isomer (Table 1, entry
7). Intriguingly, in the course of our optimization, we observed that
the regioselectivity of the directed hydrothiolation of allyl amines is
dictated by the ligand employed. As seen in Table 1, ligands with
smaller bite angles (entries 1-3) are selective for the anti-Markovni-
kov hydrothiolation product. Alternatively, those with larger bite an-
gles favor the Markovnikov isomer (entries 4-8). A similar trend is
observed when allyl imines are employed. Control reactions indicate
that the regioisomeric transformations are rhodium-catalyzed17,
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Table 2. Markovnikov-selective hydrothiolation of allyl imines and secondary allyl aminesa,b
1
2
3
4
5
6
7
5.0 equiv R3SH
3 mol % [Rh(cod)Cl]2
7.5 mol % ligand
H
0 or 1.25 equiv
NaBH4
H
H
R1
R2
(Me)2N
N
R1
N
0.5 equiv LiBr
R1
R2
N
SR3
or
R2
toluene, 80 °C, 24 h
MeOH, 0 °C to rt, 2 h
1a-s
2a-s
H
3a-s
MeO
H
H
H
OMe
H
H
Br
H
H
H
N
H
N
H
H
N
N
N
N
SPh
SPh
SPh
SPh
SPh
SPh
8
9
3a
3b
3c
3d
3e
3f
82%c, 72%d
48%d
66%c,e
72%c, 74%d
73%d
72%d
H
EtO2C
H
F3C
H
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
S
H
N
H
N
H
N
H
N
H
N
H
N
N
SPh
SPh
SPh
SPh
SPh
SPh
3l
3g
3h
3i
3j
3k
65%d
54%d
41%c,f, 41%d
70%d
73%c, 68%d
38%d
H
H
OMe
H
H
F
H
H
H
N
H
H
H
H
H
N
N
N
N
N
SPh
PMB
S
PMB
S
PMB
S
PMB
S
PMB
S
3m
58%d
3n
65%d
3o
59%d
3q
47%d
3r
59%c,g
3s
65%c, 59%d
a Isolated yields are reported as an average of two runs. b >20:1 regioselectivity is observed, as determined by NMR or GC analysis of the crude reaction
c
mixtures. Reaction conditions: (i)[Rh(cod)Cl]2 (0.012 mmol, 3.0 mol %), L1 (0.03 mmol, 7.5 mol%), LiBr (0.2 mmol, 0.5 equiv), toluene (2 M),
allyl imine
1
(0.4 mmol, 1 equiv), and thiol (2.0 mmol, 5.0 equiv) at 80 °C for 24 h. (ii) NaBH4 (0.6 mmol, 1.5 equiv), MeOH, 0 °C to rt for 2 h. d
Reaction conditions: [Rh(cod)Cl]2 (0.012 mmol, 3.0 mol %), DPEphos (0.03 mmol, 7.5 mol%), LiBr (0.2 mmol, 0.5 equiv), toluene (2 M), allyl amine
f
2
(0.4 mmol, 1 equiv), and thiol (2.0 mmol, 5.0 equiv) at 80 °C for 24 h. e 100 °C. 48 h, 7.0 equiv PhSH. g 48 h.
Table 3. Markovnikov-selective hydrothiolation of primary allyl
aminesa,b,c,d
(<5%). Unfortunately, this reaction is also limited to terminal al-
kenes, as both 1,1- and 1,2-disubstitued alkenes afforded <5% of the
desired product.
5.0 equiv PhSH
3 mol % [Rh(cod)Cl]2
A variety of thiophenol derivatives are tolerated under the reac-
tion conditions, including electron-rich (3n), sterically encumbered
(
3o), and electron-poor (3q) thiophenols. Additionally, this meth-
odology proved general for both cyclic aryl and alkyl thiols, as cyclo-
pentane and cyclohexane thiol are effective nucleophiles for the hy-
drothiolation reaction (3r-
3s). However, linear thiols (ethane thiol,
H
7.5 mol % dpph
H2N
H2N
SPh
0.5 equiv. LiBr
R
R
toluene, 80 °C, 24 h
4a-e
5a-e
H
H
H
H
H
H2N
H2N
H2N
H2N
H2N
octane thiol) do not participate in the reaction.
SPh
SPh
SPh
SPh
SPh
Ph
To our delight, primary amines are also effective directing groups
for the Rh-catalyzed hydrothiolation reaction. In addition to simple
allyl amine, as seen in Table 3, both aromatic and aliphatic substi-
tuted allyl amines proceed to afford anti-1,2-aminothioethers in
good to excellent yields as a single diastereomer (>20:1 in all
cases).19 When enantiomerically-enriched 4b was employed, the ste-
reochemical information remained with >99% enantiospecificity,
suggesting that the Rh-catalyst does not isomerize to the allylic posi-
tion.17
OMe
Cl
5b, 77%
5e, 53%f
5a, 88%
23 : 1 dr
5c, 81%
29 : 1 dr
5d, 52%
26 : 1 dr
20 : 1 dr
>99% ese
a-b See Table 2. Diastereoselectivities were determined by GC analysis
of the crude reaction mixtures. Reaction conditions: [Rh(cod)Cl]2
(0.009 mmol, 3.0 mol %), dpph (0.023 mmol, 7.5 mol%), LiBr (0.15
mmol, 0.5 equiv), toluene (2M), allyl amine
c
d
4
(0.3 mmol, 1 equiv), and
e
We next explored the anti-Markovnikov hydrothiolation of allyl
amine derivatives as a demonstration of the catalyst-controlled re-
giodivergent reaction. Although the regioselective synthesis of linear
C–S bonds from olefins has been demonstrated for over a century
with both activated and unactivated substrates via the thiol-ene re-
action20, the synthetic versatility and mechanistic implications of a
regiodivergent pathway is both advantageous and intriguing. Grati-
fyingly, both secondary and primary amines afford 1,3-aminothi-
oethers in fair to very good yields (37-74%) when dppbz is em-
ployed as the ligand (Table 4). Secondary and substituted primary
allyl amine substrates afforded the anti-Markovnikov product as a
single constitutional isomer (>20:1 a-M:M). Notably, when allyl
amine is subjected to the reaction conditions both isomers are ob-
served in a 5.5:1 of 5e':5e. Unlike the Markovnikov-selective condi-
tions, these reactions are limited to thiophenol nucleophiles.
thiol (1.5 mmol, 5.0 equiv). When starting with enantiomerically en-
riched 4a. f Isolated following boc-protection.
A variety of functional groups are well-tolerated, including p- and
o-substituted ethers (3a
3f), and an ester (3g). Heterocycles, including thiophene, furan,
and N-methyl pyrrole afforded good yields of the Markovnikov hy-
drothiolation products 3i
3k. Aliphatic amine 2l is also readily hy-
drothiolated in 65% yield. In general, decreasing the electron density
on benzyl-substituted allyl amines decreases reactivity but not selec-
,
3e), a tertiary amine (3b), an aryl bromide
(
-
tivity (3g,
3h), likely due to reduction of Lewis basicity of the direct-
ing group. Similarly, increasing the steric hindrance proximal to the
secondary amine moderately reduces the yield of 3m to 58%. Like-
wise, substitution at the α-position of the secondary allyl amine con-
sequently results in poor conversion to the hydrothiolation product
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Table 4. Anti-Markovnikov-selective hydrothiolation of allyl
are combined in THF-d8 in the presence of Bn2NH (added to act as
a surrogate for the allylic amine substrate), a Rh–H resonance is
Scheme 2. Markovnikov-selective hydrothiolation KIE studies
aminesa,b,c
1
2
3
4
5
6
7
8
5.0 equiv R3SH
3 mol % [Rh(cod)Cl]2
7.5 mol % dppbz
SR3
H
(a) initial rate KIE studies
R1HN
R1HN
5.0 equiv PhSH
or PhSD (75% D)
3 mol % [Rh(cod)Cl]2
toluene, 100 °C, 24 h
R2
2 or 4
R2
3ʹ or 5ʹ
MeO
MeO
H/D
MeO
SPh
7.5 mol % DPEphos
SPh F3C
SPh
H
H/D
N
H/D
H
N
H
N
H
SPh
9
N
N
0.5 equiv. LiBr
toluene, 80 °C
10-60 min
H
H
2a or 2a-d
3a or 3a-d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3aʹ, 50%
3dʹ, 50%
3hʹ, 37%
kH/D = 2.80 ± 0.21
S
H
S
H
H
H
N
N
PMB
OMe PMB
F
(b) Intermolecular competition KIE studies
3nʹ, 38%
3qʹ, 45%
SPh
SPh
5.0 equiv PhSH/D (50% D)
3 mol % [Rh(cod)Cl]2
H/D
S
H
MeO
H
H2N
H2N
N
H
H
N
PMB
CF3
7.5 mol % DPEphos
Ph
5bʹ, 74%, (>99% es)d
5eʹ, 43%e,f
2a and 2a-d
(50% D)
1.0 equiv
3tʹ, 45%
0.5 equiv. LiBr
toluene, 80 °C, 1.5 h
29% conversion
c
a-b See Table 2. Reaction conditions: [Rh(cod)Cl]2 (0.012 mmol, 3.0
mol %), dppbz (0.030 mmol, 7.5 mol, toluene (2.0 M), allyl amine or
2
15% D
4
(0.40 mmol, 1.0 equiv), and thiol (2.0 mmol, 5.0 equiv). d Starting with
MeO
H/D
MeO
H
H
N
enantiomerically enriched 4a. e Isolated following boc-protection. f A re-
+
N
SPh
1
gioselectivity of 5.5:1 5e':5e was observed by H NMR analysis of the
3a or 3a-d
kH/D = 5.66
crude reaction mixture.17
<5% D olefin incorporation
We hypothesize that the change in regioselectivity is an effect of
diverging coordination spheres and consequently, preferential Rh–
S or Rh–H insertion to afford branched or linear isomers, respec-
tively. We are currently investigating the coordination mode of the
complexes formed with small and large bite-angle ligands and how
those factors might affect the mechanistic divergence;17,21 however,
we have performed several experiments that offer key insight into
each catalytic cycle.
observed at –13.63 ppm (dt, J = 16.1, 11.2 Hz, 1H) in the 1H NMR
spectrum. Again, this demonstrates that oxidative addition can occur
into the PhS–H bond and that the Rh(III) hydride generated is cis
to both phosphines. Additionally, under anti-Markovnikov condi-
tions, when PhS–D is employed in intermolecular competition stud-
ies, extensive deuterium incorporation into each olefinic position of
the recovered starting material is observed (Scheme 3b). While this
precluded us from determining a competition KIE, the extensive
deuterium incorporation indicates a reversible insertion of the Rh–
H/D into the olefin (Scheme 4, step iii').17 Deuterium incorporation
at the terminal position of the olefin can be rationalized by a reversi-
Mechanistic Investigations. Our initial mechanistic studies fo-
cused on the Markovnikov-selective hydrothiolation reaction. Stoi-
chiometric investigations of [Rh(cod)Cl]2, DPEphos, and 4-meth-
oxythiophenol in THF-d8 show a Rh–H resonance at –17.2 ppm (dt,
ble Rh–H/D migratory insertion to form ', followed by b-hydride
E
elimination to form deuterated starting material.
1
J = 19.4, 18.1) in the H NMR. This observation indicates that the
Rh complex can undergo oxidative addition into the PhS–H bond to
afford a Rh(III) intermediate with the hydride cis to both phos-
phines. We next explored kinetic isotope effects (KIE) under the
Markovnikov-selective hydrothiolation conditions. Initial rate KIE
experiments performed with deuterated thiophenol (75 %-d1) are
consistent with a primary KIE (kH/kD = 2.8) (Scheme 2a); whereas,
competition experiments afford a KIE = 5.7 (Scheme 2b).22 The KIE
experiments are consistent with X–H bond breaking/forming at or
before the turnover limiting step. Further, the new C–D bond is
formed exclusively at the terminal carbon, indicating that b-hydride
elimination is not occurring after olefin insertion. Combined, this
data is consistent with (i) reversible oxidative addition into the PhS–
H/D bond followed by (ii) olefin coordination and a subsequent
(iii) slow olefin insertion into the Rh–S bond and (iv) fast reductive
elimination to form the C–H/D bond (Scheme 4, Cycle A). Transi-
tion metal-catalyzed hydrothiolations of alkynes and allenes with
group 9 metals are thought to occur through similar oxidative addi-
tion/insertion/reductive elimination steps.6a,g,h,7b
Scheme 3. Anti-Markovnikov-selective hydrothiolation KIE studies
(a) initial rate KIE studies
5.0 equiv PhSH
or PhSD (75% D)
3 mol % [Rh(cod)Cl]2
MeO
MeO
SPh
H/D
7.5 mol % dppbz
H/D
H/D
N
N
toluene, 100 °C
20-120 min
2a or 2a-d
3a' or 3a'-d
kH/D = 0.75 ± 0.15
(b) Intermolecular competition KIE studies
5.0 equiv PhSH/D (50% D)
MeO
3 mol % [Rh(cod)Cl]2
H/D
N
7.5 mol % dppbz
2a and 2a-d
(50% D)
1.0 equiv
toluene, 80 °C, 4 h
21% conversion
31% D 34% D
H/D H/D
We next performed similar investigations on the anti-Markovni-
kov-selective reaction. When [Rh(cod)Cl]2, dppp (employed for its
increased solubility relative to dppbz), and 4-methoxythiophenol
19% D
MeO
+
MeO
SPh
43% D
50% D
H/D
H/D
N
N
H/D
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Scheme 4: Proposed mechanistic divergence for the selective synthesis of 1,2- and 1,3-aminothioethers
1
2
3
4
5
L
L
H
H
ii. olefin coordination
ii'. olefin coordination
LnRh SR
LnRh SR
A
A'
i. oxidative addition
6
7
8
9
H
H
H
H
RS−H
SR
L
SR
SR
SR
L
LnRh
C
LnRh
LnRh
LnRh
C'
B
B'
L
L
Cycle A:
Markovnikov Formation
larger bite angle ligands
Cycle B:
anti-Markovnikov Formation
smaller bite angle ligands
RhLn Cl
iii. Rh−S insertion
iii'. Rh−H insertion
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
slow
RSLnRh
E'
L
E'
H
C−S reductive
SR
elimination
LnRh
LnRh
SR
L
L
H
SR
D
D'
SR
H
H
L
iv. C−H reductive elimination
iv'. C−S reductive elimination
L
H
L
SR
slow
trace
Corresponding Author
kamihull@illinois.edu
To measure a KIE under anti-Markovnikov conditions, we per-
formed initial rate KIE experiments comparing the reactivity of thi-
ophenol to deuterated thiophenol (75 %-d1). Under these condi-
tions, an inverse KIE was observed (kH/kD = 0.75 0.15) (Scheme
3a), suggesting that X–H bond making or breaking does not influ-
ence the rate of the reaction. Rather, an equilibrium isotope effect
explains the observed inverse KIE, an effect of the reversible olefin
insertion of the Rh–H/D bond. Under pre-equilibrium conditions,
the rate of product formation is affected by the equilibrium between
ACKNOWLEDGMENT
The authors would like to thank the University of Illinois for their gen-
erous support.
REFERENCES
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-d compared to
'.17 Combined, these observations are con-
B
'. The stronger C–D bond, relative to the C–H
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We have demonstrated the first catalyst-controlled regiodivergent
hydrothiolation of electronically unactivated alkenes for the selec-
tive synthesis of 1,2- and 1,3-aminothioethers. The reactions are
chemo-, regio-, and stereoselective. Initial mechanistic investiga-
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information, including optimization tables, detailed re-
action protocols, and full characterization is available free of charge on
the ACS Publications website.
AUTHOR INFORMATION
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Page 6 of 6
15
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22
The observed competition kinetic isotope effect of 5.7 may be en-
hanced due to rapid exchange between the proteo/deutero allyl amine and
thiophenol leading to Curtin-Hammett conditions; the S–D and N–D peaks
2
coalesce by H NMR at room temperature at 0.2 M (a 10-fold dilution of
reaction concentration).
H
SR3
Catalyst-Controlled,
R12N
R12N
Regiodivergent Hydrothiolation
SR3
H
R2
R2
R3S–H
+
23 examples
up to 88% yield
up to >20:1 dr
8 examples
up to 74% yield
[(P~P)RhCl]2
βn ≥ 99°
[(P~P)RhCl]2
βn ≤ 86°
R12N
R2
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