Diastereoselective Desymmetrization of p-Quinamines through Regioselective Ring Opening of Epoxides and Aziridines

Article abstract of DOI:10.1021/acs.orglett.9b04110

A highly diastereoselective desymmetrization of p-quinamines via regioselective ring opening of epoxides and aziridines under mild conditions has been developed. A chairlike six-membered transition state with minimized 1,3-diaxial interactions explains the relative stereoselectivity of the cyclization reaction. This transition-metal free [3 + 3] annulation reaction provides rapid access to fused bicyclic morpholines and piperazines with a tetrasubstituted carbon center in high yields. In addition, it also allows the synthesis of enantioenriched products by using easily accessible chiral nonracemic epoxides and aziridines.

Full text of DOI:10.1021/acs.orglett.9b04110

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diastereoselective Desymmetrization of p‑Quinamines through
Regioselective Ring Opening of Epoxides and Aziridines
Sandip B. Jadhav†,‡ and Rambabu Chegondi*,†,‡
†Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad
500007, India
‡Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
S
* Supporting Information
ABSTRACT: A highly diastereoselective desymmetrization of p-quinamines via regioselective ring opening of epoxides and
aziridines under mild conditions has been developed. A chairlike six-membered transition state with minimized 1,3-diaxial
interactions explains the relative stereoselectivity of the cyclization reaction. This transition-metal free [3 + 3] annulation
reaction provides rapid access to fused bicyclic morpholines and piperazines with a tetrasubstituted carbon center in high yields.
In addition, it also allows the synthesis of enantioenriched products by using easily accessible chiral nonracemic epoxides and
aziridines.
he development of new strategies for the selective
Recently, the desymmetrization of cyclohexadienones has
been intensively studied for the construction of highly
functionalized scaffolds in minimum operations.8 In particular,
p-quinamines (readily accessible from oxidative dearomatiza-
tion of p-anisidines)9 are a valuable subclass of cyclo-
hexadienones and utilized in various desymmetrization
approaches.10,11 Despite this, direct intermolecular [3 + 2]
or [3 + 3]-annulations of p-quinamines in a single-step with
suitable electrophiles are extremely rare in the literature.10 In
2015, Coeffard and Greck developed an organocatalyzed
desymmetrization of p-quinamines through cascade aza-
Micheal/cyclization reaction with excellent yields and
enantioselectivity.10a Later, Huang et al., reported a [3 + 2]
annulation of prop-2-ynylsulfonium salts and p-quinamines to
afford hydroindoles in moderate to good yields (Scheme
1A).10b Very recently, Sasai and co-workers developed the mild
and stereoselective Lewis base-catalyzed dual umpolung
domino cyclization of cyclohexadienones with alkynyl esters
(Scheme 1B).10c Inspired by these limited approaches and our
ongoing investigations on the desymmetrization of cyclo-
hexadienones,12 we envisioned that highly functionalized
morpholine and piperazine derivatives could easily be obtained
by utilizing the regioselective SN2-type ring opening of
epoxides or aziridines with p-quinamines followed by highly
stereoselective intramolecular oxa- or aza-Michael addition
(Scheme 1C). This reaction could provide major and minor [3
+ 3] annulation products probably via chairlike six-membered
T
formation of C−O and C−N bonds is of utmost
importance in organic chemistry.1 Over the years, numerous
C−O and C−N bond formation methods have been developed
for heterocycle synthesis based on their importance in health
care.2 In particular, heterocycles such as morpholine and
piperazine derivatives are frequently found in an array of life-
saving pharmaceuticals (Figure 1).3 A recent survey revealed
Figure 1. Examples of marketed drugs containing the morpholine and
piperazine core.
that piperazine-containing N-heterocycles occupied the third
position among the U.S. FDA-approved drugs.3a In addition,
both morpholine and piperazine motifs have also served as
organocatalysts, chiral auxiliaries, and chiral templates in
asymmetric synthesis.4 Therefore, several strategies have
emerged aimed at the synthesis of these valuable scaffolds.5,6
However, there are still several challenges to overcome
including harsh reaction conditions, multistep synthesis, costly
reagents, and poor stereoselectivity. In addition, a very limited
number of methods are available to access highly function-
alized enantiopure morpholine and piperazine derivatives.7
Received: November 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04110
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Selected Annulations on p-Quinamines and
Table 1. Optimization of the Reaction Conditions
Present Work
b
c
entry
solvent
THF
base (equiv)
tBuOk (2.0)
T (°C) yield (%) dr (3a/3a′)
1
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
rt
<10
<10
80
91
<5
<5
52
75
<10
58
67
88
78
<5
50
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
THF
THF
THF
THF
NaH (2.0)
K2CO3 (2.0)
Cs2CO3 (2.0)
NaOAc (2.0)
CsOAc (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (1.5)
Cs2CO3 (2.5)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
7:1
13:1
THF
1,4-dioxane
toluene
CHCl3
DCE
CH3CN
DMF
DMSO
CH2Cl2
THF
6:1
4:1
3:1
5:1
4:1
5:1
3:1
14:1
8:1
THF
THF
THF
90
40
20
a
Reaction conditions: 1a (0.217 mmol), 2a (0.434 mmol), solvent
b
(2.2 mL, 0.1 M). Isolated yield of both 3a and 3a′.
c
Diastereoselectivity was determined by 1H NMR on the crude
reaction mixture.
using 2 equiv of Cs2CO3 at 80 °C in THF affording 3a in 91%
yield with 13:1 diastereoselectivity (entry 4).
To evaluate the substrate scope and limitations of the
annulation reaction, various epoxides 2 were treated with 1a
under the optimized reaction conditions (Scheme 2). Excellent
levels of diastereoselectivity were observed irrespective of the
electronic and steric features of substituents on various
epoxides. Protected α-hydroxy epoxides were well tolerated
in the reaction to give corresponding morpholines 3a−c in
74−91% yield with excellent diastereoselectivity. A β-hydroxy
epoxide protected with a PMB group was also compatible with
the conditions, as morpholine 3d was isolated in 65% yield
with 9:1 dr. Alkyl-substituted epoxides smoothly underwent
the annulation to afford the corresponding products 3e−g, in
moderate yield and good diastereoselectivity. Epoxides
substituted with aromatic rings were found to afford excellent
yields and high levels of diastereocontrol regardless of
electronic features (3h and 3i). With symmetrical bis-epoxide,
selective formation of 3k took place with 1 equiv of 1a;
however, multiple products were observed with an excess
amount of p-quinamine 1a. To extend the scope of this
method for the construction of highly substituted chiral
nonracemic morpholines, various enantiopure epoxides were
reacted with 1a and the corresponding annulation products
were obtained in with excellent yield and enantioselectivity
(3l−3p).15 It is noteworthy that the annulation of glycidol
with 1a afforded the desired product 3m in higher yield and
excellent dr when compared to other protected α-hydroxy
epoxides. The use of 1,2-epoxycyclohexane under the standard
conditions was found to shut down the annulation reaction,
and both starting materials were recovered. The structures and
relative stereochemistry of the major isomer (3l) and minor
cyclic transition states TS-I and TS-II. Transition state TS-I has
less strain as compared to TS-II because of the minimization of
1,3-diaxial interactions, resulting in the major isomer.13
Epoxides and aziridines are easily available and useful building
blocks in heterocyclic chemistry.14 Moreover, this protocol
allows ring opening of chiral nonracemic starting materials to
provide enantioenriched fused bicycles. Herein, we discuss our
results in detail.
We commenced our study by examining the annulation of p-
quinamine 1a with epoxide 2a employing various bases in THF
as solvent at 80 °C (Table 1, entries 1−6). Gratifyingly, K2CO3
and Cs2CO3 provided the desired annulation product 3a in
80% and 91% yield, respectively, with good diastereocontrol
(entries 3 and 4). The use of other bases such as KOtBu, NaH,
NaOAc, and CsOAc was found to be detrimental to the
formation of annulation product 3a. Later, the influence of
nonpolar solvents and other polar aprotic solvents was also
investigated with Cs2CO3 as the base (entries 7−14).
However, these solvents did not show any improvements in
the yield and diastereoselectivity of the product. When base
loading in the reaction was decreased or increased, either
diminished reaction yield or lower diastereoselectivity was
observed (entries 15 and 16). The reaction completely shut
down at room temperature and at 40 °C gave only a 20% yield
of 3a, along with recovery of starting material (entries 17 and
18). Finally, the optimized reaction conditions were realized
B
DOI: 10.1021/acs.orglett.9b04110
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a−c
93% yield. This reaction proceeds through either the
nucleophilic ring-opening of epoxide followed by intra-
molecular SN2 displacement of a leaving group (Cl−) via a
Payne rearrangement or N-alkylation to give the undesired
epoxide 4. Interestingly, the same reaction in the presence of
K2CO3 as the base furnished desired cyclization product 3as in
83% yield with 7:1 dr (Scheme 3). Due to the higher solubility
of Cs2CO3 than K2CO3, it acts as a stronger base and facilitates
the formation of epoxide 4 probably via N-alkylation.16
Scheme 2. Substrate Scope for Epoxides
Scheme 3. Annulation of p-Quinamine with
Epichlorohydrin
Using K2CO3 as the base in the reaction, the generality of
the annulation was evaluated with variety of alkyl-, alkynyl- and
aryl-substituted p-quinamines 1 (Scheme 4). Significantly,
a−c
Scheme 4. Substrate Scope for p-Quinamines
a
Reaction conditions: 1a (0.217 mmol), 2a (0.434 mmol), Cs2CO3
b
(0.434 mmol), THF (2.2 mL, 0.1 M). Isolated yield of 3.
c
Diastereoselectivity was determined by 1H NMR on the crude
d
reaction mixtures. Isolated yields of inseparable isomers.
a
Reaction conditions: 1a (0.217 mmol), 2s (0.434 mmol), K2CO3
b
(0.434 mmol), THF (2.2 mL, 0.1 M). Isolated yield of major isomer
3. Diastereoselectivity was determined by H NMR on the crude
isomer (3l′) were confirmed by the X-ray crystallographic
analysis (Figure 2).
Subsequently, we continued to examine the reaction scope
with various p-quinamines 1 using epichlorohydrin 2s. Initially,
the treatment of 1a with 2s under optimal reaction conditions
using Cs2CO3 as a base afforded the uncyclized epoxide 4 in
c
1
reaction mixtures.
these substrates were well tolerated with epichlorohydrin 2s,
thus providing the corresponding chloromethyl substituted
morpholines 3 in high yields and high diastereoselectivities.
The increase in the steric bulk of the alkyl substituent on the p-
quinamine prochiral center led to slightly lower yields with
high diastereoselectivity (3as−3cs). In addition, the reaction of
p-quinamine substituted with propyne also proceeded
smoothly to afford the corresponding product 3ds in 70%
yield with 14:1 dr. The annulation was also effective for aryl
substituted p-quinamines to provide cyclized products 3es−
3hs with excellent diastereoselectivity.
Enticed by these results, we sought to investigate the
annulation of p-quinamines 1 with N-tosylaziridines 5 under
the optimal reaction conditions (Scheme 5). To our delight,
the reaction of chiral nonracemic iPr substituted N-
Figure 2. ORTEP of compounds 3l and 3l′.
C
DOI: 10.1021/acs.orglett.9b04110
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Annulation of p-Quinamine with N-
Tosylaziridines
Scheme 6. Synthetic Utility
a−c
a
Reaction conditions: 1 (1 equiv), 5 (1.1 equiv), Cs2CO3 (2 equiv),
b
c
THF (0.1 M). Isolated yield of 6. Diastereoselectivity was
determined by H NMR on the crude reaction mixtures. Isolated
yield of inseparable isomers.
d
1
prochiral p-quinamines followed by Michael addition. The
reaction also provides rapid access to enantiopure products by
using easily available enantiopure epoxides and aziridines. The
stereoselectivity of the annulation reaction is explained by
invoking a chairlike six-membered transition state with
minimized 1,3-diaxial interactions. Moreover, cyclization of
p-quinamines with epichlorohydrin proceeded smoothly in the
presence of K2CO3 to give the desired product, but only N-
alkylation product was observed with Cs2CO3 due to its higher
basicity. The potential applicability of this annulation reaction
was also highlighted with a gram-scale reaction. The synthetic
utility of obtained products was demonstrated with Zn-
mediated Bernet−Vasella ring-opening reaction and other
Pd(0)-catalyzed cross-coupling reactions.
tosylaziridine with alkyl- and alkynyl-substituted (Me, n-Bu
and propyne) p-quinamines gave the corresponding products
6a−6c in excellent yield with exclusive diastereoselectivity.
Similarly, other enantiopure N-tosylaziridines substituted with
Me, iBu, and Bn groups were also well tolerated, thus affording
the corresponding enantiopure piperazines 6d−6f in excellent
yields with high levels of diastereoselectivity.15 For simple N-
tosylaziridine, the desired product 6g was obtained in 85%
yield. However, annulation of N-tosylaziridines with aryl-
substituted p-quinamines at the prochiral center was not
successful.
To demonstrate the synthetic utility of the annulation
products, chloromethylmorpholine 3cs was further trans-
formed into highly functionalized cyclohexenone derivatives
(Scheme 6). Treatment of 3cs with KI at 120 °C provided
iodide 7 which on being subjected to Zn-mediated Bernet−
Vasella ring-opening reaction afforded alcohol 8 in 88% yield.
The enone functionality of the annulation products can also
serve as a synthetically valuable handle for further reactions.
When the piperazine 6a was treated with Br2/Et3N,
bromination occurred at the α-position of the enone to afford
9 in 51% yield. Subsequent Suzuki−Miyaura coupling of
bromide 9 with phenylboronic acid furnished 10 in high yield.
Sonogashira coupling of phenylacetylene with bromide 9 gave
a low yield (<10%). However, Sonogashira coupling of
phenylacetylene with iodide 11 (synthesized from the
treatment of 9 with I2/DMAP in 58% yield) gave the
corresponding enyne 12 in 86% yield. In addition, upon
treatment of compound 6a with LiAlH4 at rt, selective 1,2-
reduction occurred to give the allyl alcohol 13 in 92% yield
with >97:1 diastereoselectivity.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04110.
Experimental procedures, characterization details, 1H
and 13C NMR spectra of new compounds and X-ray
crystallographic data for representative compounds
(PDF)
Accession Codes
CCDC 1950499−1950500 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
In conclusion, we have developed a simple and highly
diastereoselective desymmetrization approach for the synthesis
of pharmaceutically important morpholines and piperazines in
excellent yields. The [3 + 3] annulation reaction proceeded via
regioselective ring opening of epoxides and aziridines with
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rchegondi@iict.res.in, cramhcu@gmail.com.
D
DOI: 10.1021/acs.orglett.9b04110
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
́
(9) Carreno, M. C.; Luzon, C. G.; Ribagorda, M. Chem. - Eur. J.
̃
2002, 8, 208−−216.
Rambabu Chegondi: 0000-0003-2072-7429
Notes
(10) For selected intermolecular annulations, see: (a) Pantaine, L.;
Coeffard, V.; Moreau, X.; Greck, C. Org. Lett. 2015, 17, 3674−3677.
(b) Xu, D.; Zhao, Y.; Song, D.; Zhong, Z.; Feng, S.; Xie, X.; Wang, X.;
She, X. Org. Lett. 2017, 19, 3600−3603. (c) Kishi, K.; Arteaga, F. A.;
Takizawa, S.; Sasai, H. Chem. Commun. 2017, 53, 7724−7727. (d) Jia,
P.; Zhang, Q.; Jin, H.; Huang, Y. Org. Lett. 2017, 19, 412−415.
(e) Kishi, K.; Takizawa, S.; Sasai, H. ACS Catal. 2018, 8, 5228−5232.
(f) Jin, H.; Dai, C.; Huang, Y. Org. Lett. 2018, 20, 5006−5009. (g) Jin,
H.; Lai, J.; Huang, Y. Org. Lett. 2019, 21, 2843−2846. (h) Zhu, Y.; Jin,
H.; Huang, Y. Chem. Commun. 2019, 55, 10135−10137. (i) Cao, B.;
Wei, Y.; Shi, M. Org. Biomol. Chem. 2019, 17, 3737−3740.
(11) For selected intramolecular annulations, see: (a) Nguyen, T. L.
N.; Incerti-Pradillos, C. A.; Lewis, W.; Lam, H. W. Chem. Commun.
2018, 54, 5622−5625. (b) Li, K.; Jin, Z.; Chan, W.; Lu, Y. ACS Catal.
2018, 8, 8810−8815. (c) Wu, W.; Chen, T.; Chen, J.; Han, X. J. Org.
Chem. 2018, 83, 1033−1040. (d) Jin, H.; Zhang, Q.; Li, E.; Jia, P.; Li,
N.; Huang, Y. Org. Biomol. Chem. 2017, 15, 7097−7101. (e) Tello-
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the CSIR-IICT and the SERB,
DST, New Delhi, India (EMR/2017/001266), for financial
support. S.B.J. thanks the University Grants Commission, New
Delhi, for a research fellowship. We gratefully acknowledge Dr.
N. Jagadeesh Babu, Department of Analytical Chemistry,
CSIR-IICT, for X-ray analysis. IICT Communication No.
IICT/Pubs./2019/330.
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