Olefin Amine (OLA) Reagents for the Synthesis of Bridged Bicyclic and Spirocyclic Saturated N-Heterocycles by Catalytic Hydrogen Atom Transfer (HAT) Reactions

Article abstract of DOI:10.1021/jacs.9b05074

Spiro- and bridged bicyclic structures are in demand for their sp³-rich frameworks that offer unique physiochemical properties and precisely positioned substituent groups. In order to rapidly access such molecules in a cross-coupling fashion we describe olefin amine (OLA) reagents for the transformation of aldehydes and ketones into all three topological types of bicyclic N-heterocycles: bridged, spiro-, and fused rings. The OLA reagents are easily prepared and allow the synthesis of complex molecular frameworks under operationally simple conditions that tolerate a wide array of functional groups. Investigations into the Mn or Fe promoted reaction pathway support a metal hydride hydrogen atom transfer (MH-HAT) to generate a C-centered radical that undergoes addition to an unactivated imine, leading to an N-centered radical. A catalytic cycle featuring regeneration of the metal catalyst by O₂ and a second HAT to form the unprotected saturated N-heterocycle appears to be operative.

Full text of DOI:10.1021/jacs.9b05074

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Article
Olefin Amine (OLA) Reagents for the Synthesis of Bridged Bicyclic
and Spirocyclic Saturated N-Heterocycles by Catalytic HAT Reactions
Ya-Yi Wang, and Jeffrey W. Bode
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 May 2019
Downloaded from http://pubs.acs.org on May 22, 2019
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Introduction
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Saturated N-heterocycles have emerged as one of the most popular and successful
scaffolds for drug design and development.1 In the past 3 years, more than 50% newly
approved small molecule drugs (FDA) feature a saturated N-heterocycle.2 While access to
substituted, saturated N-heterocycles is often challenging, a number of new synthetic
methods including intramolecular hydroamination,3 decarboxylative cross-coupling,4 and
C–H functionalization5 offer streamlined routes. In our own work, we have introduced SnAP6
and SLAP7 reagents that provide convenient access to saturated N-heterocycles from
aldehydes and ketones; these reagents are already widely used in the pharmaceutical
industry. ꢀ
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A remaining challenge is the direct synthesis of bicyclic saturated structures. As noted by
pharmaceutical experts in recent review, “Key unsolved problems in synthetic chemistry
include … concise synthesis of highly functionalized, constrained bicyclic amines”.8 Such
scaffolds are prized for their ability to position binding groups in precise, three-dimensional
orientations, which are topologically divided to three classes: spirocycles, bridged bicycles,
and fused rings. Spirocycles have become a popular scaffold for pharmaceutical
development9 and the synthesis of bridged bicyclic compounds are in high demand10 due to
their unique physiochemical properties. 11 We have therefore targeted rapid, modular
approaches to C-substituted variants of these bicyclic structures from widely available
starting materials.
In this report we document the development, synthesis, and application of olefin amine
(OLA) reagents for the synthesis of all three topological classes of bicyclic structures –
bridged bicyclic, spirocyclic and fused bicyclic saturated N-heterocycles from aldehydes and
ketones (Figure 1C).12 The reactions are initiated by a Mn or Fe catalyzed H-atom transfer
(HAT) reaction of olefins to give C-centered radicals that participate in cyclization, often via
challenging reaction trajectories. The key C–C bond forming step – HAT promoted addition
of olefins to unactivated imines – has not previously been reported. The resulting
constrained saturated N-heterocycles – particularly the bridged bicyclic N-heterocycles –
would be difficult to access by any established synthetic route.
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A. M-H catalyzed inter- and intramolecular additions to hydrazones (Baran, Bradshaw)
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4
5
6
Me
Me
Me
20 mol% Fe(acac)3
2.5 equiv PhSiH3
N
NH
Me
H
Cbz
N
EtOH, 60 °C
Argon (g)
N
Cbz
H
Me
7
8
B. M-H catalyzed, intermolecular additions to an activated imine (Shenvi)
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O
S(O)Mes
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10 mol% Fe(acac)3
3 equiv PhSi(i-PrO)H2
HN
EtO2C
S
Me
Me
N
Mes
Me
Me
DCE/i-PrOH, rt
Argon (g)
EtO2C
H
Me
C. This work: Oxygen mediated M-H catalyzed intramolecular additions to unactivated imines
O
H
O
R
R
NH
NH
O
R
O
N
Bridged Bicycles
X
H-M
NCbz
R
O
Me
O
R
N
H
O
O
N
H
R
NH2
O2
Spirocycles
Fused Bicycles
Olefin Amine
(OLA) Reagents
examples
O
NCbz
Me
Me
O
O
Ph
N
NH
NH
N
H
N
Cl
Me
O
Me
O
O
Me
O
Me
O
N
H
Et
N
H
Me
Et
N
H
CO2Et
NBoc
N
Figure 1. OLA reagents for the synthesis of C-substituted bicyclic structures.
Results
In prior work from our group, we have established that C-centered radicals, generated by
single electron oxidation of organosilicons or organostannes, undergo additions to
unactivated imines. In order to access more complicated ring structures, we sought
alternative methods for radical generation and turned to the well-known Mukaiyama
hydration of olefins13 and further developments by Carreira,14 Boger,15 Baran,16 Shenvi,17
Shigehisa,18 Herzon,19, Bradshaw 20 and others to a growing number of Mn-, Fe- and Co-
catalyzed radical hydrofunctionalizations of olefins.21 These reactions are generally based
on the Halpern mechanism22 featuring carbon-centered radicals generated from the olefins
by hydrogen atom transfer (HAT) via metal hydride (MH) species. Although both inter- and
intramolecular M–H catalyzed additions to hydrazones (Figure 1A) have been reported by
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Baran16d and Bradshaw,20b the same conditions were reportedly not suitable for additions to
simple imines.20b This is likely due to the relatively poor reactivity of unactivated imines in
radical additions, which are known to be several orders of magnitude less reactive than
hydrazones.23 Very recently, Shenvi reported M–H catalyzed intermolecular additions of
olefins to activated imines (Figure 1B),17b but our desired reactions cannot accommodate a
sulfonyl group on the imine. Furthermore, the majority of intramolecular HAT-promoted
reactions, including the elegant intramolecular additions to hydrazones, occur as 5- or 6-exo
processes, rather than the 6- or 7-endo reactions required for our target structures.
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By focusing on intramolecular reactions, we hoped to form stabilized C-centered radicals by
hydrogen-atom transfer and engage these in a cyclization to give an N-centered radical,
which could be further reduced to afford the desired saturated N-heterocycles. In order to
access the topologically challenging spiro- and bridged bicyclic structures we also required
the cyclization to occur via contorted transition states that are less kinetically accessible than
prior efforts.
Establishment of Conditions for Cyclization of OLA-Imine. For our initial studies, we
targeted the synthesis of spirocyclic morpholines with OLA reagent 1. Imine formation
between 1 and 4-fluorobenzaldehyde proceeded smoothly in the presence of the enol ether;
simple filtration and evaporation afforded the imine with no requirement for further
purification. With the readily accessible OLA-imine, we attempted the cyclization in
degassed isopropanol with catalytic amount of Fe(acac)3 (acac = acetylacetonate) and
equimolar amount of PhSiH3 as reducing reagent, under Ar or N2 atmosphere (Table 1 entry
1). These conditions, similar to Shenvi’s or Bradshaw’s for additions reactions to activated
C=N bond (Figure 1A,B), afforded only trace amounts of product from unactivated OLA-
imine. In contrast, using an air atmosphere gave desired product 11a in high yield (entry 2).
Mn(dpm)3 (dpm = dipivaloylmethane) performed better than Fe(acac)3 in most cases (entry
3), but the iron catalyst is still useful for many substrates. Further screening established that
performing the cyclization at higher temperature afforded better yields, particularly on larger
scales (entry 4). Attempts to use Buchwald’s Cu-based catalysts, which have been applied
to intramolecular additions of styrenes to imines, 24 or Co(salen) catalyst used for
intermolecular addition to phenyl sulfonyl oxime, 14b proved unsuccessful in this case. Our
screening studies highlighted the tolerance of the reaction to higher temperatures, wet
solvents, and oxygen, rendering this reaction easily executed.
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Table 1. Optimization of reaction conditions
5
6
7
8
9
5 mol% cat.
2 equiv PhSiH3
NCbz
O
NCbz
RCHO
4Å MS
O
N
O
NCbz
NH2
i-PrOH
CH2Cl2
N
H
25 oC, 12 h
1
10
11
12
13
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15
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F
F
filter, evaporation
coditions
0.2 mmol
11a
entry
yieldsa
<5%
Argon or N2, Fe(acac)3, rt
Air, Fe(acac)3, rt
1
2
78%
Air, Mn(dpm)3, rt
3
86%
Air, Mn(dpm)3, 60 oC
4b
94% (86%c)
a Yield values refer to isolated yields after purification. b Reaction with 4
equiv PhSiH3 for 8 h. c Reaction with 0.5 mmol scale
Synthesis of saturated spirocyclic morpholines. We easily prepared OLA reagents 1–3
from commercially available ketones using Lewis acid-promoted cyclic ketal opening
reaction as a key step (see SI for detailed synthetic procedures). With these reagents, we
examined the synthesis of a variety of spirocyclic morpholines 11–13 with a spirocyclic
carbon atom adjacent to the morpholine O-atom, the regioisomer of the product of SnAP
morpholine reagents with ketones.6b We tested the reactions with aryl, heteroaryl and
aliphatic aldehydes (Table 2). The reaction proceeded well with both electron-rich and
electron-poor aryl aldehydes to give moderate to good yields of the spirocyclic products and
exhibited excellent tolerance for unprotected functional groups including tertiary amines
(11c), free phenols (12b), and unprotected indoles (12d). For substrates containing aromatic
N-heterocycles (12c, 13b), we found that Fe(dibm)3 (dibm = diisobutyrylmethane) and the
inclusion of K2HPO416b – as employed by others with pyridine-containing reactants25 – gave
improved yields.
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Table 2. OLA Reagents for the synthesis of spirocycles.
5 mol% Mn(dpm)3
4 equiv PhSiH3
X
O
O
4Å MS
H
X
Air, i-PrOH
O
R
CH2Cl2,
25 oC, 12 h
NH2
60 oC, 12 h
N
H
R
1 equiv
0.5 mmol
9
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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60
NCbz
S
NH2
NH2
NH2
1
2
3
NCbz
S
O
O
O
F
N
H
N
H
N
H
F
F
11a, 86%
12a, 69%
13a, 49%
NCbz
S
O
O
O
iPr
N
H
N
H
N
H
N
OH
13b, 42%b
11b, 70%
12b, 58%
NCbz
S
N
O
O
O
N
H
N
H
N
H
NMe2
OMe
11c, 46%
12c, 45%b
13c, 51%
S
NCbz
OMe
O
O
O
CO2Me
N
H
N
H
N
H
NH
11d, 50%
12d, 44%
13d, 48%
ꢀꢀꢁꢂꢃꢄꢅꢀ&ꢆꢄ%ꢃ#ꢀ"ꢃꢇꢃ"ꢀ$ꢈꢀꢂ#ꢈꢄꢆ$ꢃꢅꢀ(ꢂꢃꢄꢅ#ꢀꢆꢇ$ꢃ"ꢀ %"ꢂꢇꢂꢉꢆ$ꢂꢈꢊꢋꢀꢁꢂꢌꢃꢍꢅꢂꢎꢏꢐꢑꢀꢂꢊ#$ꢃꢆꢅꢀꢈꢇꢀꢒꢊꢍꢅ ꢏꢐꢑꢓꢀꢔꢀꢃ!%ꢂ&ꢀꢈꢇꢀꢕꢖꢗꢂꢘꢑꢀ
ꢆꢊꢅꢀꢙꢀꢃ!%ꢂ&ꢀꢚꢛꢘꢕꢜ ꢀꢆꢅꢅꢂ$ꢂ&ꢃꢀ'ꢆ#ꢀ%#ꢃꢅꢋꢀꢝꢃꢆꢉ$ꢂꢈꢊꢀꢇꢈ"ꢀꢛ ꢀꢖꢈ%"#ꢋ
Synthesis of bridged bicyclic N-heterocycles.
Encouraged by these results, we turned to the more challenging case of bridged-bicycle
formation (Table 3). The construction of bridged bicyclic products requires the addition of
the C-radical – generated by hydrogen atom transfer – to the imine by a congested,
transannular trajectory. OLA reagent 4 was conveniently prepared from the commodity
chemical 3,4-dihydro-2H-pyran-2-methanol. In the model reaction of 4 and 4-
fluorobenzaldehyde, we found higher reaction temperatures (85 °C) were advantageous for
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forming [3.3.1]-bicyclic compound 14a in high yield. The ability to work at elevated
temperatures highlights an advantage of this system; related efforts with SnAP reagents
failed in part due to the poor stability of the copper complexes at increased temperatures.
We also tested the coupling of OLA reagent 4 with heteroaryl and aliphatic aldehydes, which
gave moderate yields of bridged bicycles 14c and 14d. In all cases, only one
diastereoisomer with the substituent group at the equatorial position of the bridged cycle
was formed, as confirmed by an X-ray structure of 14b. We also prepared OLA reagents 5
and 6 from the corresponding lactones via reduction and elimination. These reagents were
competent reaction partners with both electron-rich and electron-poor aldehydes, providing
[3.2.1]-bicyclic compounds 15 and 16 as single diastereomers in moderate to good yields.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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Table 3. OLA reagents for bridged bicycles.
( )n
5 mol% Mn(dpm)3
6 equiv PhSiH3
Y
( )n
MS 4A
H
X
Air, i-PrOH
CH2Cl2,
O
R
H2N
O
85 oC, 24 h
25 oC, 12 h
N
H
R
1 equiv
0.5 mmol
d.r.> 20:1
O
O
O
NH2
NH2
5
NH2
4
6
O
O
O
N
H
N
H
N
H
Br
Cl
F
14a, 77%
15a, 35%
16a, 53%
O
O
O
N
H
O
N
H
N
H
OMe
NMe2
N
H
Me
14b, 62%
15b, 38%
16b, 61%
Me
O
O
O
CN
N
H
N
H
N
H
Ph
N
N
14c, 35%
14d, 40%
16c, 48%
ꢀꢀꢁ ꢂꢃꢄꢀꢅꢆꢃꢇꢂꢈꢀꢉꢂꢊꢂꢉꢀꢋꢌꢀ ꢈꢌꢃꢆꢋꢂꢄꢀꢍ ꢂꢃꢄꢈꢀꢆꢊꢋꢂꢉꢀꢎꢇꢉ ꢊ ꢏꢆꢋ ꢌꢐꢑꢀ
ꢀ
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Synthesis of oligosubstituted mono- and fused- morpholines. Many of the OLA
reagents are simple to prepare – particularly in comparison to the substituted SnAP reagents
4
5
6
7
8
– rendering them attractive starting materials for stereochemically-defined substituted
morpholines. To demonstrate this, we tested simpler OLA reagents including commercially
available compound 7a and 7b, readily prepared 8 and 9 for the synthesis of di- and tri-
substituted morpholines, and reagent 10 for the synthesis of fused cycles (Table 4). These
reactions worked well and delivered the products as single diastereomers (structures
determined by crystallography and NMR). Aldehydes from aromatic N-heterocycles
including isoxazoles (17b, 19b), pyridines (18c), unprotected imidazoles (18d), and even
unprotected ketones (17a) were readily tolerated. We also found that ketones could be
employed as substrates when the ketimine formation was performed with Ti(Oi-Pr)4 and the
cyclization conducted at 85 °C to afforded disubstituted spirocyclic morpholine 18f. Medium-
sized rings are also accessible via the corresponding OLA reagents 7b and 7c, which
afforded oxazepane 21a, 21b and oxazocane 22, albeit with diminished yields as the ring
size increased.
9
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
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Table 4 . OLA Reagents for mono- and fused cycles
4
5
6
7
5 mol% Mn(dpm)3
4 equiv PhSiH3
R2
R1
R2
R1
O
O
R5
R3
R5
R4
R3
4Å MS
R4
N
H
Air, i-PrOH
O
CH2Cl2,
25 oC, 12 h
NH2
60 oC, 12 h
8
1 equiv
0.5 mmol
d.r.> 20:1
9
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
O
O
O
O
NH2
7a
Et
NH2
NH2
9
8
Me
O
Me
O
O
Me
O
F
N
H
Et
N
H
O
N
H
tBu
N
Me
H
O
17a, 50%b,c
18a, 57%c,d
19a, 60%
O
Me
O
Me
O
Me
O
N
H
Et
N
H
N
H
Ph
Me
O
N
O
N
MeO
17b, 45%
18b, 55%c,d
19b, 60%
O
Me
Me
O
O
Me
O
N
H
Et
N
H
N
H
NBoc
17c, 57%
N
Br
18c, 42%c,d
19c, 81%
O
Me
O
O
nBu
N
Et
Et
N
H
NH2
NH2
7b
NH
10
18d, 40%c,d
O
Me
O
O
Me
CO2Et
nBu
N
H
N
H
N
H
Br
OMe
20a, 41%
18e, 75%b,c,e
21a, 42%
O
O
O
Me
Me
nBu
N
H
Et
N
H
N
H
NBoc
N
Br
20b, 48%
18f, 45%c,d,f,g
21b, 33%
O
Me
O
N
H
NH2
7c
22, 29%
Cl
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ꢀꢀꢁꢂꢃꢄꢅꢀ)ꢆꢄ(ꢃ&ꢀ%ꢃꢇꢃ%ꢀ'"ꢀꢂ&"ꢄꢆ'ꢃꢅꢀ+ꢂꢃꢄꢅ&ꢀꢆꢇ'ꢃ%ꢀ#(%ꢂꢇꢂꢈꢆ'ꢂ"!ꢉꢀꢁꢂꢊꢃꢆꢈ'ꢂ"!ꢀꢆ'ꢀꢋꢌꢀ"ꢍꢉꢀꢃꢀꢊꢃꢆꢈ'ꢂ"!ꢀꢇ"%ꢀꢋ ꢀꢎꢉꢀꢄꢀꢏꢀꢃ$(ꢂ)ꢀ
3
4
5
ꢐꢎꢑꢂꢒꢓꢀ*ꢆ&ꢀ(&ꢃꢅꢉꢀꢅꢂꢔ'ꢕꢒꢀꢂ!&'ꢃꢆꢅꢀ"ꢇꢀꢆꢇꢐ%ꢕꢒꢉꢀꢈꢀꢈ"!ꢅꢂ'ꢂ"!ꢀꢇ"%ꢀꢖꢃ'ꢂ ꢂ!ꢃꢀꢇ"% ꢆ'ꢂ"!ꢗꢀꢋꢀꢃ$(ꢂ)ꢀꢘꢂꢙꢕꢆꢚꢐ%ꢛ ꢜꢀꢍꢒꢋꢍꢄꢋꢜꢀꢋꢌꢀ
"ꢍꢜꢀ ꢀꢎꢉꢀ ꢀ%ꢃꢆꢈ'ꢂ"!ꢀꢆ'ꢀꢝꢌꢀ"ꢍꢉꢀ
6
7
8
9
Telescoped synthesis of saturated rings from amino alcohols and aldehydes
In preliminary studies, we have established that morpholines and oxazepanes can be
formed by telescoping the synthesis of the OLA reagent, imine-formation, and cyclization in
a three-component coupling of aldehydes, amino alcohols, and ethyl vinyl ether.
Condensation of the amino alcohol with an aldehyde, followed by gold-catalyzed vinylation,
afforded the crude imine intermediate without further purification (Scheme 2). For the
cyclization step, we found Mn(dpm)3 was not compatible with this reaction sequence but
Fe(acac)3 promoted the synthesis of 2-Me substituted products 17d, 18g, and 21c as single
diasteroisomers in moderate yield. Although the overall yields are somewhat lower, this
tandem 3-component approach from commodity chemicals may find use in the preparation
of libraries.
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
Scheme 2. Telescoped 3-component coupling of amino alcohols, aldehydes and ethyl vinyl
ether
OH
N
OH
4Å MS
H
O
R
CH2Cl2, 12 h, r.t.
R
NH2
Au((PPh3)Cl
(2 mol%)
AgOAc
(2 mol%)
12 h, 50 oC
EtO
Fe(acac)3 (20 mol%)
PhSiH3 (4 equiv)
O
Me
O
N
Air, iPrOH
12 h, 60 oC
N
H
R
R
O
Me
O
Me
Me
O
Et
N
H
N
H
NH
21c, 25%
F
F
OMe
18g, 44%
17d, 41%
OLA reagents for the synthesis of other heterocycles and amines. These catalytic
conditions were also suitable for the synthesis of other classes of saturated N-heterocycles
from alternative OLA reagents (Scheme 3A). Starting from reagent 23, we obtained bridged
piperizine 24 as single diastereomer in good yield. OLA reagent 25 – synthesized from 1,4-
thioxane in two steps – participates in the cyclization in an unexpectedly non-selective
manner to give thiomorpholines 26a as an inseparable mixtures of diastereomers.
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Nosylation afforded products 26b and allowed us to separate and characterize the
diastereomers.
4
5
6
7
8
9
Although we were primarily focused on cyclization that occur in an endo fashion, we were
also pleased to find that these conditions could be applied to exo-cyclizations of imines
(Scheme 3B). Following the Baldwin-Beckwith rule26, the reaction of 27 and 29 lead to
secondary amines 28 and 30, respectively, as mixtures of diastereomers. These conditions
complement Bradshaw’s exo-cyclization of hydrazones,20b which afford primary amines after
reduction, by directly forming the exocyclic secondary amines.
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
Scheme 3. Other applications of OLA-imine cyclization
A. synthesis of bridged piperizine and thiomopholine
Boc
RCHO
4Å MS
5 mol% Mn(dpm)3
4 equiv PhSiH3
N
N
Boc
H2N
Air, i-PrOH
N
H
CH2Cl2
25 oC, 12 h
12 h, 85 o
C
23
F
F
24, 82%
5 mol% Mn(dpm)3
4 equiv PhSiH3
RCHO
4Å MS
S
S
Me
Air, i-PrOH
NH2
25
N
CH2Cl2
25 oC, 12
12 h, 60 oC
R
4-NsCl
Et3N
26a (R=H)
26b (R= Ns) 72%
trans:cis= 3.8:1
B. exo cyclization of olefine substituted imine
5 mol% Mn(dpm)3
4 equiv PhSiH3
Bn
Bn
HN
N
Me
Air, i-PrOH
60 oC, 12 h
5-exo
O
O
27
28, 60%
trans:cis= 2:3
Bn
Bn
HN
5 mol% Mn(dpm)3
4 equiv PhSiH3
N
Me
Air, i-PrOH
60 oC, 12 h
6-exo
O
O
29
30, 63%
trans:cis=2:1
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Mechanistic consideration. We carried out a series of control experiments to better
understand the reaction pathway, particularly the role of an oxygen-atmosphere on the
success of the cyclizations. Attempts at intermolecular coupling of simple enol ethers and
imines gave no addition products (Scheme 4A), and efforts to reduce these starting
materials with Mn(dpm)3 gave no observable reduction products. The Mn(dpm)3 catalyst
also could not promote the intermolecular coupling between enol ethers and methyl acrylate
(see SI). These observations highlight the unique relationship of Mn(dpm)3 catalyst, the
electron-rich olefin, and the imine in the successful cyclization reaction.
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
We studied the influence of various silanes and reaction conditions on the cyclization to form
17e (Scheme 4B). In the absence of i-PrOH, PhSiH3 gave poor conversion in 1,2-
dichloroethane, while Shenvi’s silane,17a PhSi(i-PrO)H2, restored the reactivity, highlighting
the need to form a more active silane. Reactions performed in degassed solvent under N2
atmosphere, instead of air, proceed to full conversion only when stoichiometric amounts of
Mn(dpm)3 were provided, revealing a key role for oxygen in catalyst turnover.17d Attempts to
use other oxidants, such as TBHP, failed to afford products under N2.
Based on extensive prior mechanistic work from Halpern, Baran, Shenvi, and others, the
reaction most likely begins by in situ generation of active metal hydride (M–H) species from
Mn (III) or Fe (III) and a silane. Metal hydride hydrogen atom transfer (MH HAT) to the
electron-rich olefin provides Mn(II) [or Fe(II)] and the heteroatom-stabilized radical II –
similar to the species postulated to be involved in SnAP chemistry. This HAT process was
demonstrated by the reaction with PhSiD3 gave deuterated product 31. Radical II undergoes
Beckwith rule26 breaking 6/7/8-endo-trig cyclization to give N-centered radical III.
Our group has demonstrated that copper or photoredox catalyzed additions of C-centered
radicals to unactivated imines requires subsequent reduction of the relatively stable N-
centered radical formed by the initial addition, a challenging process that can complicate
catalyst turnover. We initial postulated that the catalytic cycle could be completed by an
inner sphere single electron transfer between radical III and Mn (II) (Scheme 4C, Path I).
This process, however, is not likely to be operative due to the requirement of oxygen and
the large reduction potential gap between Mn (III) (E1/2III/II~ 0.39 V vs SCE) and N-centered
radical III (E1/2red = –1.70 V vs SCE for dialkylaminyl radical7). Based on this consideration,
oxidation of the catalyst and reduction of radical III are thought to be independent events.
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Scheme 4. Control experiments and proposed catalytic cycle
4
5
6
7
8
A. reduction and intermolecular addition of simple imine and vinyl ether
R1
5 mol% Mn(dpm)3
4 equiv PhSiH3
N
R2
no reduction
product observed
or
O
i-PrOH, 60 oC, 12 h
9
F
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
R1
5 mol% Mn(dpm)3
4 equiv PhSiH3
N
R2
no conversion
based on imine
O
i-PrOH, 60 oC, 12 h
F
R1= -CH2CH2OMe
R2= -CH2CH2OTBS
B. control experiments
O
O
Me
O
D
5 mol% Mn(dpm)3
2 equiv PhSiH3
N
N
H
N
H
Air, i-PrOH
60 oC, 20 min
F
F
F
31, 31% (>99% D incorp.)
PhSiD3 instead of PhSiH3
17e, 72%
Entry
Deriviation from above
Yield*
b
ClCH2CH2Cl instead of i-PrOH, 3 h
1
43%
b
PhSi(i-PrO)H2, ClCH2CH2Cl
, 3 h
2
3
4
5
66%
<5%
33%
60%
c
under N2 , 5 mol% Mn(dpm)3
c
under N2 , 50 mol% Mn(dpm)3
c
under N2 , 100 mol% Mn(dpm)3
b
a
c
yield determined by crude NMR. dry ClCH2CH2Cl used.
degassed i-PrOH used.
C. proposed catalytic cycle
O
O
Me
R
N
I
R
N
H
IV
Si-H
Si-H
Mn(III)
O2
Mn(III)-H Mn(III)-H
Mn(III)
Path II
HAT
Si-H or
Path I:
SET
Mn(III)-H
Mn(II)
Mn(II)
O
N
O
N
Me
R
H
Endo-
Radical
Cyclization
R
II
III
We therefore considered a second pathway (Path II), based on Halpern’s alkene
hydrogenation studies. The presence of active H-atom source, including both silanes and
M–H species, renders the direct reduction of III to form the final product IV by a second HAT
a probable mechanism as it is polarity matched and favored by thermodynamic
considerations (morpholine BDEN-H> 95.3 kcal/mol27 vs. PhSiH3 BDESi-H= 91.3 kcal/mol28
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vs. BDEMn-H < 50 kcal/mol17c). This double HAT pathway distinguishes it from the catalytic
redox cycle in SnAP chemistry and HAT/SET16c (or PCET)29 hybrid cycle in Fe-H catalyzed
additions of enol ethers to acrylates.
7
8
9
Conclusion
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
In summary, we have developed a convenient, modular approach to the synthesis of C-
substituted N-heterocycles including challenging bridged bicyclic and spirocyclic examples.
The catalytic reaction proceeds by a chemoselective hydrogen atom transfer reaction that
generates C-centered radicals by reduction of electron-rich olefin in the presence of imines
and a second HAT that reduces the resulting N-centered radical. Based on preliminary
experiments, the same principles should be applicable to the synthesis of other attractive
targets, including other saturated N-heterocycles and related frameworks attractive for drug
discovery.30
Supporting Information
Experimental procedures, characterization data NMR spectra for all new compounds
(PDF)
X-ray crystallographic data for 7 compounds including 14b, 18a, trans-26b, cis-26b, 32
(nosylated 15b), 33 (nosylated 19c), and 34 (nosylated 24).
Acknowledgments
In memory of Prof. Teruaki Mukaiyama. This work was supported by European Research
Council (ERC Starting Grant 306793 – CASAA) and ETH Zürich. The authors acknowledge
Dr. R. Kissner for cyclic voltammetry measurement, Dr. N. Trapp and M. Solar (SMOCC) for
acquisition of X-ray structures, and L. Bertschi (MoBiAS) for MS analysis.
References
(1)
Marson, C. M. Saturated Heterocycles with Applications in Medicinal Chemistry. Advances
in Heterocyclic Chemistry 2017, 121, 13–33.
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(2) During 2016-2018, FDA approved 86 small molecule drugs, 44 of which contained a
saturated N-heterocycle. For further information, see:
7
8
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/
9
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(3) For selected examples of intramolecular hydroamination, see: (a) Mai, D. N.; Wolfe, J. P.
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(4)
Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. Dual
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(6) For reviews, see: (a) Luescher, M. U.; Geoghegan, K.; Nichols, P. L.; Bode, J. W. SnAP
Reagents for a Cross-Coupling Approach to the One-Step Synthesis of Saturated N-
Heterocycles. Aldrichimica Acta 2015, 48, 43–48. For a recent example, see: (b) Saito, F.;
Trapp, N.; Bode, J. W. Interative Assembly of Polycyclic Saturated Heterocycles from
Monomeric Building Blocks J. Am. Chem. Soc. 2019, 141, 5544–5554.ꢀ
(7) Hsieh, S. Y.; Bode, J. W. Silicon Amine Reagents for the Photocatalytic Synthesis of
Piperazines from Aldehydes and Ketones. Org. Lett. 2016, 18, 2098–2101.
(8) Campos, K. R.; Coleman, P. J.; Alvarez, J. C.; Dreher, S. D.; Garbaccio, R. M.; Terrett, N. K.;
Tillyer, R. D.; Truppo, M. D.; Parmee, E. R. The importance of synthetic chemistry in the
pharmaceutical industry. Science 2019, 363, 244-244.
(9) Zheng, Y.; Tice C. M.; Singh S. B. The use of spirocyclic scaffolds in drug discovery. Bioorg.
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(10) Cakmak, M.; Mayer, P.; Trauner, D. An efficient synthesis of loline alkaloids Nature
Chemistry 2011, 3, 543–545.
7
8
9
(11) For selected examples of bridged cycles with unique physiochemical properties, see: (a)
Levterov, V. V.; Michurin, O.; Borysko, P. O.; Zozulya, S.; Sadkova, I. V.; Tolmachev, A. A.;
Mykhailiuk, P. K. Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine
Analogues with Improved Water Solubility and Reduced Lipophilicity. J. Org. Chem. 2018,
83,14350–14361 (b) Degorce, S. L.; Bodnarchuk, M. S.; Cumming I. A.; Scott J. S. Lowering
Lipophilicity by Adding Carbon: One-Carbon Bridges of Morpholines and Piperazines. J.
Med. Chem. 2018, 61, 8934–8943.
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20
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24
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26
27
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47
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(12) During the submission of this manuscript, Gaunt reported an elegant synthesis of N-
protected spirocyclic amines by cyclization of iminiums and olefins under visible-light
promoted photoredox catalysis and a Hantzsch ester as the HAT reagent: Floden, N. J.;
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ꢀꢁ
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TOC graphic:
O
O
O
R
R
NH2
NH
NH
O
N
OLA Reagents
Bridged Bicycles
•H
NCbz
R
Me
H
O
R
•H
N
H
O
O
R
O
N
H
R
Mn or Fe catalyzed
HAT
Spirocycles
Fused Bicycles
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