C-H Functionalization of Amino Alcohols by Osmium Tetroxide/NMO or TPAP/NMO: Protecting Group-Free Synthesis of Indolizidines (–)-223AB and 3-epi-(–)-223AB

Article abstract of DOI:10.1002/ejoc.201901494

The oxidative cyclization of amino alcohols by osmium tetroxide/NMO or tetrapropylammonium perruthenate (TPAP)/NMO was found to provide an N,O-acetal moiety through the trapping of the resulting iminium ion by the alcohol. These two transformations were demonstrated in the synthesis of indolizidines (–)-223AB and 3-epi-(–)-223AB.

Full text of DOI:10.1002/ejoc.201901494

A Journal of
Accepted Article
Title: C-H Functionalization of Amino Alcohols by Osmium Tetroxide/
NMO or TPAP/NMO: Protecting Group-Free Synthesis of
Indolizidines (-)-223AB and 3-epi-(-)-223AB
Authors: Wei-Lun Chen, Lee-Ya Wang, and Yu-Jang Li
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901494
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901494
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10.1002/ejoc.201901494
European Journal of Organic Chemistry
COMMUNICATION
C-H Functionalization of Amino Alcohols by Osmium
Tetroxide/NMO or TPAP/NMO: Protecting Group-Free Synthesis
of Indolizidines ()-223AB and 3-epi-()-223AB
Wei-Lun Chen,[a] Lee-Ya Wang,[a] and Yu-Jang Li*[a]
Abstract: The oxidative cyclization of amino alcohols by osmium
tetroxide/NMO or tetrapropylammonium perruthenate (TPAP)/NMO
was found to provide an N,O-acetal moiety through the trapping of
the resulting iminium ion by the alcohol. These two transformations
were demonstrated in the synthesis of indolizidines ()-223AB and
oxidation by OsO4/NMO or TPAP/NMO.
Table 1. Reaction conditions for the oxidation of 1a with OsO4/NMO.[a]
3-epi-()-223AB
.
x mol% OsO4
N
N
y eq. NMO
solvent
OH
O
H
1a
2a/3a
The functionalization of a carbon adjacent to a tertiary
amine nitrogen via
C(sp3)-H activation has been
developed over the past decade, and such methods include
oxidative cross-dehydrogenative coupling (CDC)
Entry
1
OsO4, mol%
NMO, eq
Yield (%)[b]
a
2
2
1
2
3
3
3
3
3
3
3
0
60 (28)
62 (23)
80
2
reactions,[1,2] electro-oxidative activations and photoredox
reactions.[3,4] In these processes, the generated iminium
cations are important intermediates for the subsequent C-C,
C-O and C-N bond formations. In particular, the formation
of a C-O bond by the addition of an oxygen nucleophile to
the iminium cation gives an N,O-acetal moiety. Such
manipulation can simultaneously activate and protect a
specific carbon, thus providing greater efficiency and
flexibility for subsequent synthetic transformations. Since
the N,O-acetal moiety can be assembled or cleaved
whenever carbon activation or subsequent functionalization
is needed, tedious protection/deprotection steps in the
synthetic sequence can be avoided.
3
2
4
4
89
5
6[c]
6
88
4
60
7
1
64 (28)
55 (36)
N.R.
8
8
0.1
0
9
10
100
[a] Unless otherwise indicated, the reaction was carried out using 0.4 mmol of
1a (0.3 M) in THF/H2O (10:1), OsO4 (2.5% in t-BuOH) was added at ambient
temperature, and the mixture was stirred for 1 hour. [b] The isolated yield, with
the yield of recovered 1a shown in parentheses. [c] ACN/H2O (10:1) as the
reaction solvent.
Unfortunately, existing N,O-acetal generation strategies
involving the trapping of oxygen by the iminium cation are
better suited to the addition of phenolic oxygens via
Cu(OAc)2, Ag2O or I2/H2O2 mediated oxidations (Scheme
1a),[5,6,7] or reactions of aryl aldehydes/aryl alkyl ketones
with amines under metal and oxidant free conditions
(Scheme 1b).8 The limited examples involving nonphenolic
hydroxyl groups include the electro-oxidative cyclization or
a
Cu(OAc)2, n=1, 2
R
R
or
Ag2O,n=1,2,3, R=Ph
or
N
N
N
I2/ H2O2, n=1,2, R=Ph or H
n
n
n
OH
O
R
b
R
Toluene, w 145 oC, n=1,2,3
HN
or
O
o
+
AcOH (1 equiv), 4A MS
phH, 60 oC, n=1,2,3
n
OH
O
KI/ NaOMe, current
n=0, m=2 or n=1, m=1
or
Ir(ppy)2(dtb-bpy)PF6, h
n=2, m=0 or n=0, m=2
c
Ir(ppy)2(dtb-bpy)PF6
hydroquinoyl and hydroisoquinoyl alcohols (Scheme
1c),[4b,4c] and FeCl3
catalyzed
photooxidation
of
n
N
n
N
O
m
HO
R
m
[
9
]
[ 10 ]
d
or CHDFe(CO)3
mediated
R
FeCl3, T-HYDRO
n=1 or 2, x=2, R= H
or
Me3NO, CHDFe(CO)3
N
N
n
oxidations of saturated amino alcohols (Scheme 1d). Herein,
we disclosed two novel and general procedures for the
oxidative cyclization of saturated amino alcohols. When
amino alcohols 1a and 1b were used as test substrates, we
were surprised to find that a catalytic amount of OsO4 with
n
n
x
OH
x
O
e: This Work
R1
n=1, x=1, R= alkyl
R2
R3
R1
R2
R3
x
OsO4/NMO
N
N
x
OH
or
O
n
TPAP/NMO
n=1,2,3/ X=1,2
NMO or
a catalytic amount of tetrapropylammonium
Scheme 1. Formation of cyclic N,O-acetals: a) oxidation involving phenolic
alcohols; b) metal and oxidant free conditions; c) formation by electrooxidation
and photooxidation processes; d) oxidation from saturated amino alcohols; e)
perruthenate (TPAP) with NMO are efficient reagents for
this transformation (Scheme 1e). Although studies related
to the oxidation of tertiary amines by OsO4 or ruthenium
oxidants have been reported, oxidations with OsO4
generally resulted in complicated mixtures of amides,[11] and
oxidations using RuCl2(PPh3)3/t-BuOOH or RuCl3/O2/NaCN
[a]
W.-L. Chen, L.-Y. Wang, Prof. Y.-J, Li*
Department of Applied Chemistry
gave the corresponding
-oxygenation or -cyanation
products,[12] studies related to the intramolecular trapping of
alcohols to form N,O-acetals involving the use of OsO4 or
ruthenium oxidants have not been reported. In our initial
study of OsO4/NMO (Table 1), treatment of 1a with OsO4 (2
mol%) and NMO (1 eq) provided a mixture of isomers 2a/3a
National Chiayi University
300 Syuefu Road, Chiayi City, Taiwan 60004
E-mail: yjli@mail.ncyu.edu.tw
Homepage: https://www.ncyu.edu.tw/chem_eng/content.aspx?
site_content_sn=7692
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201901494
European Journal of Organic Chemistry
COMMUNICATION
N
Os(VIII) / Ru(VII)
in 60%. When the amount of NMO was increased to 2 and
3 equivalents, the products were obtained in 62% and 80%
yields, respectively (Entries 2 and 3). Increasing the loading
of OsO4 (4-6 mol%) also improved the yield from 80% to
approximately 88-89% (Entries 4-5), but the effect was not
as great as that of increasing the NMO loading. Changing
the solvent from THF to acetonitrile gave a lower yield
(60%). When the OsO4 loading was decreased to 1 and 0.1
mol%, the products were obtained in 64% and 55% yields,
respectively (Entries 7 and 8). In the absence of OsO4, no
reaction occurred (Entry 9). Nevertheless, when one
equivalent of OsO4 but no NMO was used in the reaction,
the reaction proceeded slowly and provided the products in
8% yield (Entry 10).
OH
NMM
NMO
N
A
A-Os/ A-Ru
N
N+
O-
Os(VI) / Ru(V)
OH
B
H
H
N+
O
N+
O
O
O
O
or
O-
O-
Os
Ru
N
O-
H
H
O-
O-
O
C
A-Os
A-Ru
Scheme 2. Plausible mechanism for the oxidative cyclization.
Table 3. Reaction conditions for the oxidation of 1a-p with OsO4/NMO
and TPAP/NMO.[a]
Table 2. Reaction conditions for the oxidation of 1b with TPAP/NMO.[a]
R
R
x mol% TPAP
N
A. OsO4, NMO
N
H
N
N
n
OH
y eq. NMO
CH2Cl2
n
or
OH
O
O
B. TPAP, NMO
H
1b
2b/3b
1 a-p
Entry
TPAP, mol%
NMO, eq
T (h)
Yield (%)[b]
23 (43)
50 (18)
75
Entry
Amine[b]
T (h)
Product[c]
Yield[%][d]
1
2
3
4
5
6
1
2
2
2
2
2
2
0
2
2
4
4
4
4
R
R
R
N
H
N
N
2
OH
O
O
H
5
75
1
2
3
4
5
6
1a (R=t-Bu)
1b (R=i-Pr)
1c (R=n-Pr)[e]
1d (R=i-Bu)
1
0.75
6
4
6
4
6
4
12
5
2a/3a
2b/3b
2c/3c
2d/3d
2e/3e
A. 89(100:0)
B. 79(100:0)
A. 72(85:15)
B. 75(83:17)
A. 80(83:17)
B. 82(83:17)
A. 75(81:19)
B. 75(81:19)
A. 67(84:16)
B. 65(85:15)
A. 65(80:20)
B. 89(80:20)
8
76
100
19 (45)
[a] The reaction was carried out using 0.4 mmol of 1b (0.3 M) in CH2Cl2, and
TPAP was added at ambient temperature. [b] The isolated yield with the yield
of recovered 1b shown in parentheses.
When studied under TPAP/NMO conditions (Table 2), the
treatment of 1b with TPAP (1 mol%) and NMO (2 eq) for 2
hours provided 2b/3b in 23% yield, and 43% of 2a was
recovered (Entry 1). When 2 mol% TPAP was used, the
yield increased to 50%, but 18% of 1b remained (Entry 2).
By increasing the reaction time to 4 hours, the products
were obtained in 75% yield (Entry 3). Increasing the TPAP
loading to 5 mol% and 8 mol% did not further increase the
yield, and the products were obtained in yields of 75% and
76%, respectively (Entries 4 and 5). When one equivalent
of TPAP and no NMO were used, the reaction gave 19% of
2b/3b, 30% of the corresponding aldehyde and 45% of
recovered 1b (Entry 6). The above two reactions showed
that; 1) both OsO4 and TPAP are required respectively for
the transformation, and 2) a lower loading of TPAP relative
to OsO4 can provide complete conversion. A plausible
mechanism (shown in Scheme 2) was proposed to explain
1e (R=Bn)
1f (R=Ph)
R
12
5
2f/3f
R
R
N
H
N
H
N
OH
O
O
7
8
1g (R=t-Bu)
1h (R=i-Bu)
1i (R=i-Pr)
1j (R=Bn)
1k (R=Ph)
R
1
3
4
6
4
6
6
6
6
6
4g/5g
4h/5h
4i/5i
4j/5j
4k/5k
R
A. 70 (41:59)
B. 67 (40:60)
A. 65 (60:40)
B. 70 (65:35)
A. 65 (67:33)
B. 72 (67:33)
A. 70 (80:20)
B. 67 (80:20)
A. 72 (91:9)
B. 71 (88:12)
9
10
11
R
N
N
H
N
OH
O
O
H
12
13
14
15
1l (R=i-Bu)
1m (R=Bn)
1n (R=Ph)
0.5
6
0.5
6
0.5
6
24
48
6l/7l
A. 71 (63:37)
B. 69 (63:37)
A. 73 (65:35)
B. 80 (62:38)
A. 75 (71:29)
B. 72 (75:25)
A. 75
-
the transformation facilitated by OsO4 or RuO4 with NMO.
-
6m/7m
6n/7n
The amino alcohol (
intramolecular (as shown in A-Os
deprotonation by NMM to afford the iminium cation (
Os(VI) or Ru(V) species, respectively. The generated
iminium cation ( ) was cyclized by hydroxyl group to the
N,O-acetal product ( ), and Os(VI) or Ru(V) species were
A
) was oxidized by OsO4 or RuO4 , via
/
A-Ru) or intermolecular
) and
B
Ph
Ph
H
Ph
H
B. 45(81:19) [f]
N
B
N
CHO
CHO
O
C
H
HO
-
1o
8 + RCHO
transformed back to OsO4 and RuO4 to re-enter the
catalytic cycle by NMO.
Ph
Ph
H
Ph
16
24
48
A. 72
H
B. 36 (47:53) [f]
N
N
O
H
HO
1p
9 + RCHO
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10.1002/ejoc.201901494
European Journal of Organic Chemistry
COMMUNICATION
Pr
N
TBSO
Pr
TBSO
TBSO
OTBS
OTBS
[a] Conditions A: 0.4 mmol of substrate (0.3 M) in THF/H2O (10:1) and 4 mol%
of OsO4 (2.5% in t-BuOH) with 3 eq. of NMO; Conditions B: 0.4 mmol of
substrate (0.3 M) in CH2Cl2 and 2 mol% of TPAP with 2 eq. of NMO. [b].
Unless otherwise indicated, S isomers were used. For the synthesis of 1a-p,
see the ESI. [c] Relative configurations of the two diastereomers were
determined by 2D-NOESY analysis (see the ESI). [d] Yield of the isolated
product after column chromatography, the diastereomeric ratios were
determined by 1H NMR (400 MHz) analysis. [e] The R isomer was used. [f]
Ratio of product to aldehyde as determined by 1H NMR.
N
OsO4 (6 mol%)/NMO(4 eq.)
6 h, THF, H2O, 10:1
OH
O
H
10
12
13
83% (12:1)
OTBS
Pr
OTBS
Pr
TBSO
A. OsO4 (6 mol%)/NMO(4 eq.)
N
N
6 h, THF, H2O, 10:1
A. 84% (2.3:1)
B. 53% (3.3:1)
or
O
OH
H
11
B. TPAP/ NMO
Me
H
Me
R
O
HO
O
O
O
H
OsO4 (4%), NMO(3 eq.)
THF/H2O, 10:1
H
N
We subsequently explored the substrate scope of the
reaction with cyclic amines with different substituents and
ring sizes (Table 3). The reactions of various substituted
N
H
R
H
H
O
O
15a, R = H, 68%
15b, R = Me, 74%
14a/b
O
amino alcohols, including pyrrolidineethanols 1a
-1f,
Scheme 3. Oxidative cyclizations of 10, 11, and 14a/b
piperidineethanols 1g 1k and azepaneethanols 1l-n with 4
-
mol% OsO4 and 3 eq. NMO (conditions A) and with 2 mol%
TPAP and 2 eq. NMO (conditions B) afforded oxidative
cyclization products 2a/3a to 6n/7n in moderate to good
yields (Entries1-14). Notably, 1) TPAP/NMO conditions
were found to be more effective than OsO4/NMO conditions
in the oxidative cyclization of five-membered ring
pyrrolidineethanols 1a-f, 2) the rates of the oxidative
cyclizations under OsO4/NMO conditions were proportional
to the size of the nitrogen-containing ring, that is, azepane
ring > piperidine ring > pyrrolidine ring, which indicated that
the greater conformational flexibility is beneficial to the
oxidation process, and 3) the rates of the oxidative
cyclizations under TPAP/NMO conditions were less
sensitive to the size of the nitrogen-containing ring, which
might due to the less bulky volume of ruthenium oxide
relative to osmium oxide. The reactions of homologous
alcohols 1o and 1p under OsO4/NMO conditions gave
moderate yields (Entries 15 and 16), due to entropy, they
reacted much more slowly than 1f and 1k, respectively
(Entries 6 and 11); the reactions gave significantly lower
yields under TPAP/NMO conditions. In both cases,
Figure 1. Structure of 15b obtained by X-ray crystallography.
nPr
nPr
nPr
A: 2eq. BuMgBr,
16a/16b = 1 : 3, 87%
N
N
N
H
+
OH
OH
nBu
B: 2eq. BuMgBr,
1.5 eq. MAD,
16a/16b = 3 : 1, 75%
O
nBu
16a
2c/3c
16b
nBu
nBu
H
H
H nPr
H2
H nPr
Bun
+
H nPr
H2
3
3
3
H
H2
TPAP (2 mol%)
NMO (3 eq.)
N
N
N
H
cinnamaldehyde was obtained via the elimination of
-
+
H2
H2
H2
O
O
O
amino aldehydes generated by the competitive oxidation of
the alcohol under TPAP/NMO conditions.
H
H
17a
17a'
17b
When compounds 10 and 11 with more substituents on the
pyrrolidinemethanol fragment were subjected to OsO4/NMO
conditions with higher OsO4 loading (6 mol%), 3,3,5-
trisubstituted hexahydropyrrolo[2,1-b]-1,3-oxazole 12 and
4,4,6-trisubstituted hexahydro-2H-pyrrolo[2,1-b]-1,3-oxazine
13 were obtained in 83% and 84% yields, respectively. The
reaction of 11 under TPAP/NMO conditions was
complicated by the oxidation of the alcohol but still provided
13 in a moderate yield (53%). Notably, when two alkene-
tethered cyclic amines 14a/b were subjected to the
OsO4/NMO conditions, diastereospecific products 15a/b
were obtained in moderate yields, presumably as a result of
the strong coordination in the OsO4/NMO-mediated alkene
dihydroxylation and oxidative cyclization (Scheme 3). The
17a + 17a'/17b =3 : 1, 17a + 17a'(53%), 17b(19%)
17a + 17a'/17b =1 : 3, 17a + 17a'(20%), 17b(56%)
R1
R2
nPr
2 R1
R
nPr
H2
H2
allylMgCl
N
N
H
O
O
H
Mg
allyl
R3
17a/17a', R1=Bu, R2=H, R3= H
17b, R1=H, R2=Bu, R3= -H
Cl
18a, R1=Bu, R2=H
18b, R1=H, R2=Bu
nPr
nPr
2 R1
2 R1
R
R
1)SO3.Pyridine/
DIPEA
OH
N
H
N
Grubbs' cat.
2)Wittig Rxn
H
19a, R1=Bu, R2=H (85%)
19b, R1=H, R2=Bu (87%)
20a, R1=Bu, R2=H (74%)
20b, R1=H, R2=Bu (85%)
nPr
nPr
nPr
2 R1
H
Bu
Bu
H
R
H
structures of 12, 13 and 15a/b were determined by 2D
H2, Pd/C
90%,92%
5
3
N
N
H
N
3
3
NOESY experiments (see the ESI), and the structure of 15b
was confirmed by X-ray crystallography, as shown in Figure
1.[13]
8a
H
H
21a, R1=Bu, R2=H (82%)
21b, R1=H, R2=Bu (82%)
( )-223AB
3-epi-( )-223AB
Scheme 4. Synthesis of ()-223AB and 3-epi-()-223AB
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10.1002/ejoc.201901494
European Journal of Organic Chemistry
COMMUNICATION
The iterative C(sp3)-H activation of cyclic amines to afford the
N,O-acetals by Ag2O following alkyl Grignard addition has been
applied in the synthesis of ,’-disubstituted cyclic amines.[14]
We envisioned that the opening of aminal 2c/3c by an alkyl
Grignard following the second activation/Grignard addition can
provide the 2,5-disubstituted pyrrolidine intermediate needed for
the synthesis of 3,5-disubstituted indolizidine 223AB.[ 15 , 16 , 17 ]
Therefore, the synthesis of 223AB and a related analogue
commenced with the ring opening of 2c/3c by an alkyl Grignard.
Although the reaction with simple butyl Grignard afforded
inseparable mixtures of 16a/b (87%) in 1/3 ratio, the addition of
methylaluminum bis(2,6-di-tert- butyl-4-methyl phenoxide (MAD)
with the Grignard reagent reversed the preference and resulted
in a 3/1 ratio (75%). The reactions of both mixtures of 16a/b
under TPAP/NMO conditions provided separable 17a/17a’ and
17b in 20%/56% and 53%/19% yields, respectively. The
structures of 17a and 17b were determined by 2D NOESY
experiments (see the ESI). The reactions of 17a/17a’ and 17b
with allyl Grignard afforded 19a (85%) and 19b (87%)
This work was supported by the Ministry of Science and
Technology of Taiwan (MOST 106-2113-M-415-001, 107-2113-
M-415-005). The support from the mass spectrometer facility
provided by the National Chung Hsing University is
acknowledged.
Keywords: asymmetric catalysis, C-H functionalization,
oxidative cyclization, osmium tetroxide, TPAP.
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respectively
with
high
diastereoselectivities.
Iminium
intermediates 18a/18b, avoiding the A1,3-strain, were proposed
to account for the facial selectivity during the Grignard
addition,[18] as this effect outweighed the steric effects involving
the existing butyl group on the pyrrolidine ring. Ley-Griffith
oxidation following the methylene olefination of 19a and 19b
gave 20a and 20b in 74% and 85% yields, respectively. Ring-
closing metathesis of dienes 20a and 20b gave 21a and 21b in
82% and 82% yields, respectively, and the final hydrogenation of
21a and 21b using palladium on carbon under a hydrogen
atmosphere completed the synthesis of alkaloid ()-223AB (90%,
[]30 93.2 (c 0.5, MeOH), lit.[16o] []20 85.0 (c 0.42, MeOH))
D
D
and 3-epi-()-223AB (92%, []28 13.2 (c 0.2, MeOH), lit.[17b]
D
[3] (a) M. Okimoto, T. Yoshida, M. Hoshi, K. Hattori, M. Komata, K.
Numata, K. Tomozawa, Heterocycles 2006, 68, 25632570; (b) M.
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Tomozawa, Aust. J. Chem. 2007, 60, 236242.
[]23 11.1 (c 0.2, MeOH)). The NMR data of synthetic
D
indolizidines ()-223AB and 3-epi-()-223AB were consistent
with the reported data (Scheme 4).
[4] (a) M. Rueping, S. Zhu, R. M. Koenigs, Chem. Commun. 2011, 47,
1270912711; (b) J. Xuan, Z.-J. Feng, S.-W. Duan, W.-J. Xiao, RSC
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42604265.
In summary, we report here the general oxidative
cyclization of amino alcohols with OsO4/NMO or
TPAP/NMO conditions to afford cyclic N,O-acetal
compounds in moderate to good yields. The most obvious
benefit of these two reactions is to functionalize the carbon
neighboring the nitrogen and to protect the latent
functionality in one step. A tandem dihydroxylation/oxidative
cyclization reaction was discovered when an alkene-
substituted cyclic amine was subjected to the OsO4/NMO
reaction conditions. Finally, the synthetic potential of these
two transformations was demonstrated via sequential
oxidative cyclization/Grignard addition reactions in the
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protecting group-free synthesis of indolizidines (
)-223AB
and 3-epi-( )-223AB.

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[13] CCDC 1941078 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
Acknowledgments
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10.1002/ejoc.201901494
European Journal of Organic Chemistry
COMMUNICATION
structures.
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10.1002/ejoc.201901494
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
C-H Functionalization
R3
R1
Bu
Pr
R1
R3
R2
R2
OsO4/ NMO
or
TPAP/ NMO
Wei-Lun Chen, Lee-Ya Wang and Yu-
Jang Li*
N
N
H
N
x =1,2
n=1, R'= Pr
x =1,2
OH
O
n =1,2,3
16 examples
up to 89% yield
n =1,2,3
Page No. – Page No.
Indolizidine ( )-223AB / 3-epi-( )-223AB
C-H Functionalization of Amino
Alcohols by Osmium Tetroxide/NMO
or TPAP/NMO: Protecting Group-Free
Synthesis of Indolizidines ()-223AB
and 3-epi-()-223AB
Efficient protocols for the oxidative cyclizations of amino alcohols by two of the
platinum group metal oxides, namely osmium tetroxide and tetrapropylammonium
perruthenate with NMO, were found to provide N,O-acetal moieties by trapping the
resulting iminium ion with the alcohol. These two transformations were
demonstrated in the protecting group-free synthesis of poison-dart frog indolizidines
()-223AB and 3-epi-()-223AB.
This article is protected by copyright. All rights reserved.