Oxidations of pyrrolidines and piperidines to afford CH-functionalized isopropyl-1-carboxylate congeners

Article abstract of DOI:10.1016/j.tetlet.2021.152978

This article describes the action of iodine(III) reagents [diacetoxyiodobenzene, PhI(OAc)₂, and iodosobenzene, (PhIO)_n] in conjunction with TMSBr which act as functional bromine equivalents in unique oxidations of saturated, carbamate protected N-heterocycles. Interestingly, during this work, treatment of the same carbamates with molecular bromine alone afforded similar products, which were sequestered by the solvent methanol.

Full text of DOI:10.1016/j.tetlet.2021.152978

Tetrahedron Letters 69 (2021) 152978
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidations of pyrrolidines and piperidines to afford CH-functionalized
isopropyl-1-carboxylate congeners
a
a
a
a,b,
⇑
Steven Gunawan , Nathan Bedard , Christopher Foley , Christopher Hulme
a
Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, United States
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85737, United States
b
a r t i c l e i n f o
a b s t r a c t
Article history:
2
This article describes the action of iodine(III) reagents [diacetoxyiodobenzene, PhI(OAc) , and iodosoben-
Received 15 December 2020
Revised 1 March 2021
Accepted 3 March 2021
Available online 17 March 2021
n
zene, (PhIO) ] in conjunction with TMSBr which act as functional bromine equivalents in unique oxida-
tions of saturated, carbamate protected N-heterocycles. Interestingly, during this work, treatment of the
same carbamates with molecular bromine alone afforded similar products, which were sequestered by
the solvent methanol.
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Hypervalent iodine
N-acyliminium
Bromination
Radical
N-bromosuccinimide
CH-functionalization
Introduction
Iminiums such as 1 (Fig. 1) are one of the most important elec-
trophiles in synthetic organic transformations for the creation of
carbon–carbon and carbon–heteroatom bonds. Covalent attach-
ment of electron withdrawing groups at the nitrogen atom
enhances its cationic character making the species a more reactive
intermediate (Fig. 1) [1,2]. Amongst these modified cations, much
interest has centered around N-acyliminium ions 2 and 3, although
ureas 4, N-tosyl derivatives 5, and hydrazonium ions 6 have also
been studied [1]. The importance of N-acyliminium ions 2 and 3
has been demonstrated in a multitude of natural product syntheses
Fig. 1. Iminium ion and its derivatives.
Of particular interest is the use of hypervalent iodine reagents,
thus named due to their ability to possess more than eight elec-
trons in the valence shell as required by the octet rule [24]. Two
oxidation states dominate the field - iodine(III) and iodine (V)
[25–27]. The most widely-used iodine(V) compounds are Dess-
Martin periodinane [28] and o-iodoxybenzoic acid (IBX) [29]. Con-
versely, iodine(III) reagents are categorized into five classes: (1)
[
3–5] and exploited in secondary reactions on multi-component
reaction products leading to the formation of unique small mole-
cules [6–8].
iodosylarenes (ArIO) and their acyclic derivatives (ArIX
2
) (2) five-
Typically, N-acyliminium ions or their precursors are generated
in situ, being commonly prepared via direct oxidative electrochem-
ical methods [9–12], reduction of lactams or imides through
hydride addition [1,2,13–17], ring closure of linear amides [18–
membered iodine heterocycles (benziodoxoles, and benzioda-
zoles), (3) iodonium salts (R I X ), (4) iodonium ylides (ArI = CR ),
2 2
and (5) iodonium imides (ArI = NR) [27] where each reagent has
different chemical properties and synthetic applications. Iodosy-
larenes have broad utility as oxidizing reagents [27].
+
-
2
0], cuprous ion-promoted decomposition of o-diazobenzamides
21], and chemical oxidation by means of iodine(III) and TMSX
X = N , Cl) reagent combinations [22,23].
[
(
Of particular note is a series of elegant applications of the
(PhIO)
isopropylsilyl (TIPS) enol ethers [22,30–32]. Further studies
demonstrated that (PhIO) and TMSN enabled the direct -azido-
n 3
/TMSN reagent combination for the b-azidonation of tri-
3
n
3
a
⇑
Corresponding author at: Department of Pharmacology and Toxicology, College
of Pharmacy, The University of Arizona, Tucson, AZ 85737, United States.
nation of amides, carbamates, and ureas (Scheme 1) [33], repre-
senting the first direct chemical oxidation of N-protected
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
https://doi.org/10.1016/j.tetlet.2021.152978
0
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

S. Gunawan, N. Bedard, C. Foley et al.
Tetrahedron Letters 69 (2021) 152978
observed with the urea derivative (n = 1, X = NPh
-azido product 8 in high yield [33].
The downside of Magnus’ -azidonation protocol is the instabil-
ity of the putative reactive intermediate PhI(N which decom-
poses to iodobenzene and 3 mol of N (g) with sporadic violent
explosions [23]. Interestingly, oxidative applications of Will-
gerodt’s reagent (PhICl ) [23,34] on the same starting materials
2
) which afforded
a
a
3 2
)
2
2
were subsequently reported. Encouragingly, treatment of carba-
mate 9 with a modified version of Willgerodt’s reagent (dichloro
(
4-nitrophenyl)iodane, 10) afforded the surprising a,b,b-oxidation
Scheme 1.
tions: (i) (PhIO)
n = 2 11–41% yield) or IBX (2.4 eq.), TMSN
yield; n = 2, 15–85% yield).
a
-Azidonation of amides, carbamates, and ureas. Reagents and condi-
(2.4 eq.), TMSN (4.8 eq.), CH Cl , –40 to –25 °C (n = 1 25–82% yield,
(4.8 eq.), CH Cl , reflux (n = 1, 32–64%
product 11 (R = OH) (Scheme 2). Addition of 5% MeOH to the sol-
vent produced 11 (R = OMe) (80% yield) via ionization of 11 to
the N-acyliminium ion and solvent trapping. A similar oxidation
n
3
2
2
3
2
2
2 2
to a methoxy dichloride with tert-Butyl hypochlorite in CH Cl :
MeOH has been reported in which an N-acyliminium intermediate
was proposed [35].
pyrrolidine and piperidines to products which were readily ionized
to N-acyliminium ions. Use of two different iodine(III) reagents
As such, this clearly suggested that the study of alternate
(
n
(PhIO) and IBX) revealed a slower rate of a-azidonation and
(
PhIO)
n
/TMSX combinations was warranted, in particular the reac-
14 [36] (Scheme 3). Espe-
lower yield of products from the piperidine series 7 (n = 2) than
with the pyrrolidine 7 (n = 1) series. Optimal conversions were
tivity of the short-lived species PhIBr
2
cially when photochemical oxidations to ethoxy dibromo species
have been demonstrated with pyrrolidine-2-ones [37].
Results and discussion
Pilot studies utilized the acid-stable carbamate 15 to avoid
deprotection by HBr, a side product of the expected reaction. Thus,
Scheme 2.
a,b,b-Oxidations of carbamates. Reagents and conditions: (i) 10 (4–5 eq.),
MeCN, 45 °C (85% yield) (1 h) or MW 150 °C (5 min) (71% yield).
2
Scheme 3. In situ generation of PhIBr .
Fig. 2. X-ray crystal structure of 16.
Table 1
n
Reaction optimization using (PhIO) and PIDA hypervalent iodine reagents.
Entry
Solvent
CH Cl
MeCN
T
t
Ph(IO)
n
(eq.)
PhI(OAc)
2
(eq.)
TMSBr (eq.)
Yield 16 (%)
1
2
3
2
2
0 °C to r.t.
0 °C to r.t.
–60 °C
0 °C to r.t.
80 °C
0 °C to r.t.
60 °C
80 °C
80 °C
80 °C
80 °C
120 °C
120 °C
120 °C
120 °C
19.5 h
17.5 h
3 h
20 h
5 min
5 d
20 min
5 min
10 min
20 min
20 min
20 min
20 min
20 min
20 min
2
2
2
10
2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
4
4
4
4
4
4
1
2
3
4
4
4
4
20
4
8
8
8
8
8
8
2
4
6
8
9%
3%
5%
6%
CH
CH
CH
CH
CH
CH
CH
CH
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
a
4
b
5
22%
40%
48%
48%
62%
69%
39%
14%
35%
56%
65%
6
7
8
9
10
11
12
13
14
15
MeCN
CH
CH
CH
CH
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
a
5
2
6% starting material was recovered.
2% starting material was recovered.
b
2

S. Gunawan, N. Bedard, C. Foley et al.
Tetrahedron Letters 69 (2021) 152978
Table 2
Scope of substrates.
or using an excess of reagents (Table 1, entry 4). However,
improvement was observed after microwave irradiation at 80 °C
for 5 min (Table 1, entry 5), (22% yield, 22% recovered starting
material). The use of phenyliodine(III) diacetate (PIDA) 17 with
TMSBr [39] afforded a significant improvement in the yield of 16
Substrate
n
Product
Yield (%)
18
19
20
2
3
4
21
22
23
76
62
56
2
Scheme 4. Decomposition of PIDA/TMSBr to PhI and Br .
n
exposure of 15 to Ph(IO) 12 (2 eq.) and TMSBr (4 eq.) afforded the
a,b,b-oxidized product 16 albeit in low yield (Table 1, entry 1) (0 °C
to rt, o/n). Nonetheless, unequivocal structural confirmation of 16
was provided by X-ray crystallography (Fig. 2) [38]. The yield
was not improved upon changing the solvent to MeCN (Table 1,
entry 2), lowering the temperature to –60 °C (Table 1, entry 3),
Scheme 5. Proposed radical mechanism for the
oxidations.
a,b- and
a,b,b-carbamate
Table 3
Bromination of carbamate 15.
Entry
Solvent
T
t
Br
2
(eq.)
Product
Yield (%)
1
2
3
4
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
80 °C
120 °C
80 °C
80 °C
1 h
3
3
5
6
16
16
16
24
43
41
46
39
20 min
20 min
1 h
MeOH
Table 4
Scope of the bromination.
Entry
Substrate
n
R
Br
2
(eq.)
Product
Yield (%)
NR
1
2
3
4
25
26
27
27
2
1
1
1
Ph
6
3
3
6
28
29
30
30
a
O-tBu
O-Bn
O-Bn
0
11
b
c
15
NR = no reaction.
a
No recovered product or starting material.
b
c
5
5
2% recovered starting material.
% recovered starting material.
3

S. Gunawan, N. Bedard, C. Foley et al.
Tetrahedron Letters 69 (2021) 152978
Table 5
Radical bromination.
Entry
Starting material
R
T
t
NBS (eq.)
AIBN (eq.)
Product
Yield (%)
0a
30
41
1
2
3
26
27
15
O-tBu
O-Bn
O-iPr
65 °C
80 °C
80 °C
reflux, 4 h
MW, 1 h
MW, 1 h
1.05
10
10
0.05
0.5
0.5
29
30
24
b
a
No recovered starting material or desired product.
b
3
2% recovered starting material.
to 40% (5 d, rt) (Table 1, entry 6). Subsequent yields after micro-
wave irradiation continued to improve with prolonged reaction
time from 5 to 20 min at 80 °C, ranging from 48 to 69% (Table 1,
entry 8–10) with dichloromethane superior to acetonitrile (Table 1,
entry 11). Stoichiometry studies at elevated temperature (Table 1,
entries 12–15) demonstrated linear yield improvements. The scope
of the reaction was also demonstrated by the use of different sub-
strates (Table 2), proving compatible with 6-, 7- and 8-membered
rings.
n
bromine from Ph(IO) and TMSBr, furnishes 31 [10,21]. Subsequent
formation of a-bromo-carbamate 32 follows which is readily ion-
ized to 33. b-proton removal furnishes enamide 34 and evolution
of hydrobromic acid. Enamide reaction with bromine readily
affords the b-Br N-acyliminium ion 35. The latter is trapped by
methanol to give the
ophilic aprotic solvent (CH
bromo-enamide 36 to the b,b-dibromo-N-acyliminium ion 37,
which upon basic work-up furnishes the final ,b,b-product 16.
Intrigued by the N-acyl- -hydroxy-b,b-dibromo-functionality,
a,b-product 24. Conversely, in a non-nucle-
2
Cl ), the reaction proceeds through
2
a
During the reactions, we observed the rapid formation of a dark
a
orange color which was repeated upon mixing (PhIO)
n
or PIDA
sub-structure searching on Scifinder revealed no precedents,
although Reaxys revealed apparent reports by Leuchs 100 years
ago detailing the action of molecular bromine on a strychnine ana-
log [44]. In this case, an acyl-pyrrolidine ring is formed upon rear-
with TMSBr in CH Cl and deemed indicative of the generation of
2
2
molecular bromine. Indeed, prior reports describe the intermediate
derived from the PIDA/TMSBr reagent combination decomposing
to iodobenzene and bromine after only 5 min (Scheme 4) [40]. This
clearly suggested that study of molecular bromine as a potential
rangement of a strychnine derivative, to afford two open
methylene carbon atoms primed for further reaction with molecu-
lar bromine to afford the -hydroxy-b,b-dibromo- congener. Irre-
a- and b-
oxidant was warranted, assuming that (PhIO)
tional equivalent. Indeed, when 15 was treated with bromine in
CH Cl and irradiated at 80 °C for 1 h, product 16 was isolated
43% yield) (Table 3, entry 1) suggesting the occurrence of photo-
bromination [41] in conjunction with or, more likely, in place of
the assumed action of PhIBr 14. At an elevated temperature or
n
/TMSBr was a func-
a
spective of this report, we feel that publication of this non-
electrochemical transformation on simple ‘deconstructed’ satu-
rated nitrogen heterocycles warrants reporting.
2
2
(
2
when excess bromine was employed (Table 3, entry 2 and 3), com-
parable yields of 16 were attained. However, when the reaction
Conclusion
was conducted in a nucleophilic solvent (MeOH), a new
a,b-oxi-
Herein, we report new oxidation chemistry mediated by hyper-
valent iodine(III) reagents in conjunction with TMSBr to furnish a-
hydroxy-b,b-dibromine functionalized N-isopropyloxy protected
pyrrolidines and piperidines. Moreover, additional studies demon-
strate that molecular bromine promotes these transformations,
with yields improved through use of NBS and the radical initiator
dized product 24 was isolated (39% yield) (Table 3, entry 4). It is
important to note that when an amide was used as the starting
material (N-benzoyl-piperidine), no conversion was observed
(Table 4, entry 1). Similarly, no product was furnished when
employing Boc-protection (Table 4, entry 2), presumably due to
the production of HBr (Scheme 5) with subsequent starting mate-
rial and/or product decomposition. Cbz-protection proved amen-
AIBN. In addition, the
a-methoxy-b-bromine derivative of N-iso-
propyloxy-pyrrolidine was produced when utilizing a methanolic
bromine solution.
able to
a,b-oxidation albeit in low yield (Table 4, entry 3 and 4).
This was also not surprising as N-Cbz deprotection is known to
occur with HBr in glacial acetic acid [42,43].
With this data in-hand, it seemed likely the transformation
would also occur upon exposure to N-bromosuccinimide (NBS)
and the radical initiator azoisiisobutyronitrile (AIBN) (Table 5).
As such, Boc-protected pyrrolidines afforded no discernible prod-
ucts (Table 5, entry 1). Conversely, N-Cbz-pyrrolidines furnished
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
the
the corresponding yield with methanolic bromine (Table 4, entry
and 4). Finally, the reaction of N-isopropyloxy-pyrrolidine 15
with NBS/AIBN, produced 24, isolated in comparable yield (41%)
to treatment with Br in MeOH (Table 5, entry 3).
a,b-product 30 in 30% yield (Table 5, entry 2), higher than
3
Acknowledgments
2
A mechanism was proposed to explain formation of the
observed products (Scheme 5). Exposure of carbamate 15 to either
i) NBS and AIBN (ii) molecular bromine or (iii) in situ generated
The authors thank Dr. Gary S. Nichol for X-ray crystallography
work (Structure 16, CCDC 769990) and the National Institutes of
Health (P41GM086190 to CH) for financial support.
(
4

S. Gunawan, N. Bedard, C. Foley et al.
Tetrahedron Letters 69 (2021) 152978
[
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oxidations of carbamates with Willgerodt-like hypervalent iodine reagents—
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