Expedient and rapid synthesis of 1,2,3-triazolo[5,1-c]morpholines through palladium-copper catalysis

Article abstract of DOI:10.1021/jo900428j

A one-pot approach using palladium - copper as catalyst has been developed for the synthesis of morpholines fused with 1,2,3-triazole. Good regioselectivity, mild reaction conditions, high yields and short reaction time are the hallmarks of this method.

Full text of DOI:10.1021/jo900428j

fused triazoles are of interest due to their various biological
activities4 and also clinical applications5 (viz. alprazolam,
estazolam, etc.). On the other hand, the morpholine moiety is
found in a diverse range of bioactive agents including antide-
pressant, antileukemia, NK-1 receptor antagonist, fungicide, etc.6
For example, reboxetine6a is used as an antidepressant drug to
treat clinical depression, attention deficit disorder, panic disorder,
hyperactivity, etc., and fenpropimorph6d is extensively used in
agriculture as a fungicide, mainly to control fungal attacks in
cereals. Presently the world drug index contains more than 100
drugs having this structural feature in different forms including
scaffold, side-chain, fused-ring, etc. The reason behind the
extensive use of the morpholine core by pharmaceutical
industries is primarily the likely improvement in pharamaco-
kinetics effected by this structural unit. Therefore, it would be
attractive to develop a straightforward and convenient method
for the synthesis of morpholines fused with 1,2,3-triazole, which
would pave the way for the preparation of a wide variety of
different bioactive compounds. Although there are numerous
methods for the synthesis of individual 1,2,3-triazoles7 and
morpholines,8 only a few methods exist in the literature for some
specific 1,2,3-triazolo-morpholine analogs,9 adopting multistep
procedures through conventional reaction pathways. Therefore,
there remains a need for a scalable, efficient, and general method
for this important class of compounds, particularly using
transition-metal-catalyzed one-pot reactions.
Expedient and Rapid Synthesis of
1,2,3-Triazolo[5,1-c]morpholines through
Palladium-Copper Catalysis
Chinmay Chowdhury,* Sanjukta Mukherjee, Bimolendu Das,
and Basudeb Achari
Chemistry DiVision, Indian Institute of Chemical Biology
(unit of CSIR), 4, Raja S. C. Mullick Road, JadaVpur,
Kolkata 700032, India
chinmay@iicb.res.in
ReceiVed February 25, 2009
A one-pot approach using palladium-copper as catalyst has
been developed for the synthesis of morpholines fused with
1,2,3-triazole. Good regioselectivity, mild reaction conditions,
high yields and short reaction time are the hallmarks of this
method.
In the course of our research activities directed toward the
synthesis of various heterocycles10 of biological interests using
Because of the abundance of medium-sized heterocyclic
scaffolds in many natural products, drugs, and preclinical leads,
synthesis of these compounds through novel methodologies that
achieve the formation of multiple bonds in one operation is one
of the major challenges in organic synthesis. Such processes
need to avoid multiple steps, protection and deprotections, drain
of resources, and long reaction times, thereby constituting
environmentally benign and atom-economic methods. To this
end, use of a catalytic amount of transition metals to trigger
the process is being recognized as a powerful means. In this
context, one particular area that has witnessed significant interest
over the past few years is azide-alkyne cycloaddition. The
importance of this reaction was enhanced significantly after the
discovery of “click-reaction”.1
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Among the approaches to C-C and/or C-N bond-forming
reactions leading to various heterocycles, 1,2,3-triazoles have
received special interest because of their potent use ranging from
medicinal chemistry2 to material science.3 More importantly,
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conventional thermal cycloaddition approach. For details, see:(a) Oliva, A. I.;
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3612 J. Org. Chem. 2009, 74, 3612–3615
10.1021/jo900428j CCC: $40.75 2009 American Chemical Society
Published on Web 04/03/2009

TABLE 1. Scope of the Reaction for the Synthesis of
SCHEME 1. Synthesis of 1,2,3-Triazolo[5,1-c]morpholines
through Palladium-Copper Catalysis
1,2,3-Triazolo[5,1-c]morpholinesa
palladium catalyst, we have reported in the recent past the
synthesis of 1,2,3-triazolo-isoindolines.10a This led us to envis-
age that O-propargylated-2-azidoethanol 1 would react with
various aryl/vinyl iodides 2 under palladium-copper catalysis
leading to carbon-substituted morpholines 3-5 fused with 1,2,3-
triazoles (Scheme 1). The present report addresses several key
issues related to azides: (a) their reactivity toward metal activated
internal alkynes, (b) their regioselectivity in intramolecular
cycloaddition that normally does not adjust to the structural
requirements required for “click chemistry”, and (c) the optimum
catalytic reaction conditions. Herein we report our results
obtained so far toward these goals.
At the outset, the reaction of 1a with iodobenzene 2a was
tried under our previously reported10a reaction conditions
[Pd(PPh3)2Cl2/CuI/Et3N/115 °C], expected to give the desired
product 3a. However, this produced the product in low yield
(37%). This disappointing result prompted us to optimize the
reaction conditions and catalysts. After screening various types
of palladium catalyst (for details see Supporting Information),
Pd(OAc)2/PPh3 along with CuI turned out to be the most
effective catalytic system. Omission of either CuI or PPh3
resulted in very low yield or no formation of desired products.
Among the bases (inorganic and organic) and solvent systems
examined, K2CO3 and DMF turned out to be superior compared
to others. Resorting to heating without initial stirring for the
requisite time period at room temperature lowered the product
yields. The optimized reaction conditions were applied subse-
quently for the reactions between azido-alkynes 1a-c and
iodides 2a-k resulting in the products 3-5 (entries 1-14, Table
1). The aryl, heteroaryl, and vinyl iodides employed in the
reactions worked efficiently, furnishing good to excellent yields.
Unfortunately, aryl bromides did not respond as coupling partner
in these reactions. The reaction tolerated many functional groups
including methoxy, carbomethoxy, methyl, trifluoromethyl,
fluoro, nitro, etc. The presence of electron-withdrawing groups
(EWGs) in the iodides 2 ensured better yields compared to
electron-donating groups (see Table 2, entries 4, 5, 10, 14 vs 6,
11). Similarly, alkyne-azides 1a-c having various substitutions
were also found to be equally effective in our reaction
conditions. Indeed, a single diastereomeric product 5 was
obtained in the case of diphenyl-substituted alkyne-azide 1c (see
Table 2, entries 12-14). In contrast to the outcome (1,4-
disubstituted triazole) of “click reaction”, our method yielded
regioselectively 1,5-disubstituted triazoles. No extrusion of
nitrogen was observed during the course of the reaction.11
To investigate the scope of the reactions further, azido-alkynes
1a-b were treated with 1,4-diiodobenzene 6 under these
reaction conditions. Gratifyingly, the bis-heteroannulated prod-
ucts 7a-b were formed regioselectively with good yields
(Scheme 2). Thus, this method could also be applied for the
synthesis of fascinating molecules having poly heteroannulated
frameworks under one-pot reactions.
a Reaction conditions: 1 (1.2 equiv), 2 (1.0 equiv), Pd(OAc)2 (0.05
equiv), PPh3 (0.20 equiv), CuI (0.10 equiv), K2CO3 (2.0 equiv),
n-Bu4NBr (0.05 equiv) in dry DMF (5 mL) stirred at rt for 45 min and
then heated at 100 °C for 1 h. b Satisfactory spectroscopic and analytical
data were obtained for all new products. c Azido-alkyne 1c and products
5a-c are all in recemic mixture.
intramolecular cycloaddition in preference to intermolecular
cycloaddition, which would have led to cyclodimerization.12 The
The structures of all new products were well secured by
spectroscopic and analytical data. Mass spectral data supported
(12) (a) Angell, Y.; Burgess, K. J. Org. Chem. 2005, 70, 9595. (b)
Chandrasekhar, S.; Rao, C. L.; Nagesh, C.; Reddy, C. R.; Sridhar, B. Tetrahedron
Lett. 2007, 48, 5869.
(11) Feldman, K. S.; Iyer, M. R. J. Am. Chem. Soc. 2005, 127, 4590.
J. Org. Chem. Vol. 74, No. 9, 2009 3613

SCHEME 2. Synthesis of Bis-heteroannulated Products
7a-b
hydrogen that needs to be carried out in the next step by the
employed base. Upon deprotonation, a palladium-acetylide
complex C is formed, which undergoes reductive elimination15c
to afford the acyclic intermediate D with regeneration of
palladium(0), which makes the catalytic cycle active. The acyclic
intermediate D would presumably be converted17 to the desired
cyclized product 3-5 through the copper-coordinated intermedi-
ate E. DMF could facilitate the cycloaddition as it is a dipolar
aprotic solvent.
SCHEME 3. Plausible Reaction Mechanism
In conclusion, the aforementioned heteroannulation involves
a two-step process carried out in one pot: (a) palladium(0)-
catalyzed coupling reaction resulting in internal alkynes, fol-
lowed by (b) copper(I)-catalyzed intramolecular cycloaddition
between azide and internal alkyne, leading to 1,2,3-triazolo[5,1-
c]morpholines 3-5. In conjunction with other recent reports,18
this method could expand the scope of “click chemistry”, where
cycloaddition of azide is applicable to terminal alkynes only.
The reaction process was found to be general and highly
regioselective, furnishing an array of compounds with moderate
to excellent yield, starting from readily available or easily
synthesized simple materials. The method is operationally simple
and requires a short reaction time period. We believe this
methodology should find broad applications in synthetic, com-
binatorial, and medicinal chemistry as well.
cis-stereochemistry of products 5a-c was established through
NOE between the adjacent protons of morpholine ring in
NOESY spectra as well as their small coupling constants (∼2-3
Hz) in 1H NMR. Finally, the unambiguous structural confirma-
tion came from X-ray diffraction analysis of a representative
product 5b (see structure in Supporting Information). Interest-
ingly, careful scrutiny of the vicinal H-H coupling constants
in morpholine ring of products 3 and 4 reveals that the J values
are small (∼4-5 Hz) in products 3 but distinctly different
(∼10-11 Hz) in products 4. This observation suggests that the
phenyl ring adjacent to the nitrogen prefers to adopt an axial-
like conformation, whereas that next to the oxygen takes up
the equatorial conformation.13 The above structural conclusion
was further supported by X-ray diffraction analysis of another
product 3d (see structure in Supporting Information).
A possible reaction mechanism, which accounts for the
formation of products 3-5, is shown in Scheme 3. In this
connection, it is worth mentioning that the corresponding acyclic
intermediates D were isolated with 65% and 88% yields,
respectively, when the reactions of 1a and 1b were performed
separately with phenyl iodide 2a at room temperature for 45
min under the optimized reaction conditions but without using
copper iodide. On the basis of this evidence, we believe that
the formation of the intermediate internal alkyne D is not
proceeding through conventional Sonogashira’s coupling path-
way14 involving CuI; rather, it is following a palladium(0)-
catalyzed copper-free Sonogashira pathway15 as depicted in
Scheme 3. The palladium(0) formed in situ16 undergoes oxida-
tive addition with aryl (or vinyl) iodides 2 to form RPd(II)I
(A), which subsequently activates the triple bond of 1 through
coordination as in intermediate species B. Activation of the triple
bond is necessary15b for deprotonation of the acetylenic
Experimental Section
General Procedure for the Synthesis of 1,2,3-Triazolo[5,1-
c]morpholines (3-5). A mixture of Pd(OAc)2 (5 mg, 5 mol %)
and PPh3 (22 mg, 20 mol %) in dry DMF (4 mL) was stirred for
10 min under argon atmosphere. Iodo-compound 2 (0.416 mmol),
K2CO3 (115 mg, 0.833 mmol), and tetrabutylammonium bromide
(7 mg, 5 mol %) were added to it successively. The whole reaction
mixture was then allowed to stir for another 10 min under argon
atmosphere. A solution of azido-acetylene 1 (0.499 mmol) in dry
DMF (2 mL) was added dropwise followed by CuI (8.0 mg, 10
mol %). The resulting mixture was flushed with argon carefully
and stirred at room temperature for 45 min. After disappearance
of starting materials (monitored by TLC), the whole mixture was
allowed to heat at 100 °C for 1 h. Upon completion of the reaction,
the solvent was removed in vacuum; the residue was mixed with
water (10 mL) and then extracted with ethyl acetate (3 × 15 mL).
The combined organic extracts were washed with brine (10 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The resulting residue was purified through silica
gel(100-200mesh)columnchromatography(ethylacetate-petroleum
ether) to afford the desired product.
3,7-Diphenyl-6,7-dihydro-4H-[1,2,3]triazolo[5,1-
c][1,4]oxazine (3a). White solid (75 mg, 65% yield): mp 160-161
1
°C; H NMR (CDCl3, 300 MHz) δ 4.12 (dd, J ) 5.1, 12.0 Hz,
1H), 4.31 (dd, J ) 4.0, 12.0 Hz, 1H), 5.18 (d, J ) 15.0 Hz, 1H),
5.27 (d, J ) 15.0 Hz, 1H,), 5.69 (t, J ) 4.2 Hz, 1H), 7.17-7.19
(m, 2H), 7.36-7.38 (m, 4H), 7.47 (t, J ) 7.4 Hz, 2H), 7.69 (d, J
) 7.2 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 59.7, 63.4, 69.9,
126.0, 126.8, 127.7, 127.8, 128.5, 128.7, 128.8, 130.6, 136.6, 140.9;
IR (KBr) 3029, 2931, 2838, 1607, 1493, 1456 cm-1; MS (FAB)
m/z 278 [M + H]+. Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45;
N, 15.15. Found: C, 73.71; H, 5.52; N, 15.19.
(13) This perhaps arises from the fact that the axial N-C-Ph does not face
any 1,3-diaxial interaction while it also avoids the 1,2-torsoinal strain with the
neighboring N-N bond.
(14) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467. (b) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(15) (a) Ljungdahl, T.; Bennur, T.; Dallas, A.; Emtena¨s, H.; Ma¨rtensson, J.
Organometallics 2008, 27, 2490. (b) Cheng, J.; Sun, Y.; Wang, F.; Guo, M.;
Xu, J.-H.; Pan, Y.; Zhang, Z. J. Org. Chem. 2004, 69, 5428. (c) Soheili, A.;
Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.; Hughes, D. L. Org. Lett.
2003, 5, 4191. We thank the referee for bringing ref 15a to our attention.
(16) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992, 11,
3009.
(17) Intermediate species D (R ) R1 ) Ph, R2 ) H) was isolated, and several
control experiments were carried out under various reaction conditions. However,
expected cycloaddition was completed within 1 h (with 91% yield of desired
product 3a), when the aforementioned intermediate D was heated in DMF at
100 °C in the presence of catalytic amount (10 mol %) of CuI only. Heating at
100 °C without CuI yielded the desired product 3a (54%) along with the recovery
of unreacted intermediate D (41%) even after 14h.
(18) (a) Majireck, M. M.; Weinreb, S. M J. Org. Chem. 2006, 71, 8680. (b)
Zhang, C-T.; Zhang, X.; Qing, F.-L. Tetrahedron Lett. 2008, 49, 3927.
3614 J. Org. Chem. Vol. 74, No. 9, 2009

3-(2-Carbomethoxyphenyl)-7-phenyl-6,7-dihydro-4H-[1,2,3]tri-
azolo[5,1-c][1,4]oxazine (3e). White solid (99 mg, 71% yield): mp
124-126 °C; H NMR (CDCl3, 300 MHz) δ 3.81 (s, 3H), 4.09
3-(3-Methoxyphenyl)-6,7-diphenyl-6,7-dihydro-4H-[1,2,3]tria-
zolo[5,1-c][1,4]oxazine (5b). White solid (142 mg, 89% yield): mp
196-197 °C; 1H NMR (CDCl3, 300 MHz) δ 3.90 (s, 3H), 5.30 (d,
J ) 3.0 Hz, 1H), 5.34 (d, J ) 15.6 Hz, 1H), 5.62 (d, J ) 15.3 Hz,
1H), 5.85 (d, J ) 3.0 Hz, 1H), 6.64 (d, J ) 7.2 Hz, 2H), 6.93 (dd,
J ) 1.9, 8.2 Hz, 1H), 7.01-7.02 (m, 2H), 7.08 (t, J ) 7.3 Hz,
2H), 7.14-7.23 (m, 5H), 7.38-7.43 (m, 2H); 13C NMR (CDCl3,
75 MHz) δ 55.3, 63.5, 64.3, 78.7, 111.1, 113.9, 118.2, 126.0, 127.4,
127.71, 127.74, 128.01, 128.08, 130.0, 132.1, 134.3, 135.8, 140.4,
1
(dd, J ) 5.5, 12.1 Hz, 1H), 4.33 (dd, J ) 4.2, 12.0 Hz, 1H), 4.92
(d, J ) 15.3 Hz, 1H), 5.0 (d, J ) 15.0 Hz, 1H), 5.70 (t, J ) 4.6
Hz, 1H), 7.18-7.21 (m, 2H), 7.34-7.43 (m, 3H), 7.46-7.51 (m,
2H), 7.57-7.62 (m, 1H), 7.94 (d, J ) 7.8 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 52.2, 59.9, 63.1, 70.4, 126.8, 128.4, 128.6,
128.8, 129.3, 130.2, 130.6, 130.8, 131.7, 136.8, 140.3, 167.8; IR
(KBr) 2987, 2952, 2849, 1715, 1591, 1495, 1452 cm-1; ESI-MS
m/z 335.94 [M + H]+, 357.92 [M + Na]+, 373.89 [M + K]+. Anal.
Calcd for C19H17N3O3: C, 68.05; H, 5.11; N, 12.53. Found: C, 68.18;
H, 5.22; N, 12.44.
160.0; IR (KBr) 3063, 3034, 2938, 2839, 1599, 1495, 1458 cm-1
;
ESI-MS m/z 405.97 [M + Na]+. Anal. Calcd for C24H21N3O2 C,
75.18; H, 5.52; N, 10.96. Found: C, 75.11; H, 5.61; N, 11.03.
3-(4-Trifluoromethylphenyl)-6,7-diphenyl-6,7-dihydro-4H-
[1,2,3]triazolo[5,1-c][1,4]oxazine (5c). White solid (135 mg, 77%
yield): mp 249-250 °C; IR (KBr) 3038, 2851, 1620, 1454, 1121
3-(2-Methyl-4-nitrophenyl)-6-phenyl-6,7-dihydro-4H-[1,2,3]tri-
azolo[5,1-c][1,4]oxazine (4c). Light yellow solid (95 mg, 68%
1
cm-1; H NMR (CDCl3, 300 MHz) δ 5.31 (d, J ) 2.4 Hz, 1H),
1
yield): mp 141-142 °C; H NMR (CDCl3, 300 MHz) δ 2.58 (s,
5.37 (d, J ) 15.6 Hz, 1H), 5.65 (d, J ) 15.3 Hz, 1H), 5.87 (d, J )
2.1 Hz, 1H), 6.66 (d, J ) 7.5 Hz, 2H), 7.01-7.03 (m, 2H), 7.09 (t,
J ) 7.3 Hz, 2H), 7.16-7.24 (m, 4H), 7.75 (d, J ) 8.1 Hz, 2H),
7.86 (d, J ) 8.1 Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ 63.5,
64.4, 78.9, 126.04,126.08,127.7,127.8, 128.1, 128.2, 129.5, 129.9,
134.1, 134.3, 135.6, 139.4; ESI-MS m/z 422.11 [M + H]+, 444.08
[M + Na]+, 460.07 [M + K]+.Anal. Calcd for C24H18F3N3O C,
68.40; H, 4.31; N, 9.97. Found: C, 68.36; H, 4.42; N, 10.06.
3Η), 4.39 (dd, J ) 11.1, 12.9 Hz, 1H), 4.81 (dd, J ) 3.0, 13.2 Hz,
1H), 4.98 (dd, J ) 3.0, 10.5 Hz, 1H), 5.06 (d, J ) 15.3 Hz, 1H),
5.17 (d, J ) 15.3 Hz, 1H), 7.35 (d, J ) 8.4 Hz, 1H), 7.46 (br, 5H),
8.10 (d, J ) 8.4 Hz, 1H), 8.19 (s, 1H); 13C NMR (CDCl3, 75 MHz)
δ 20.9, 51.2, 62.6, 75.4, 120.9, 125.8, 126.0, 128.8, 128.9, 129.1,
129.8, 136.1, 136.5, 139.1, 139.7, 147.3; IR (KBr) 3073, 2938,
1592, 1512, 1448 cm-1; ESI-MS m/z 337.01 [M + H]+, 358.99
[M + Na]+. Anal. Calcd for C18H16N4O3: C, 64.28; H, 4.79; N,
16.66. Found: C, 64.35; H, 4.86; N, 16.54.
Acknowledgment. This work was partially supported by Net-
work projects IAP-0001 and NWP-0009. Thanks are due to Dr.
R. Mukhopadhyay, Mr. E. Padmanaban, and Mr. K Sarkar for
spectral analysis. B.A. thanks CSIR (New Delhi, India) for an
EMS grant.
3-(3-Methoxyphenyl)-6-phenyl-6,7-dihydro-4H-[1,2,3]triazo-
lo[5,1-c][1,4]oxazine (4d). White solid (78 mg, 61% yield): mp
141-142 °C; IR (KBr) 2994, 2944, 2842, 1596, 1497, 1458, 1076
1
cm-1; H NMR (CDCl3, 600 MHz) δ 3.86 (s, 3H), 4.28 (dd, J )
10.5, 12.9 Hz, 1H), 4.66 (dd, J ) 3.0, 13.2 Hz, 1H), 4.86 (dd, J )
3.3, 10.5 Hz, 1H), 5.13 (d, J ) 15.0 Hz, 1H), 5.33 (d, J ) 15.0
Hz, 1H), 6.89 (dd, J ) 1.8, 8.4 Hz, 1H), 7.08 (d, J ) 7.8 Hz, 1H),
7.33-7.36 (m, 2H), 7.40-7.42 (m, 1H), 7.44(d, J ) 4.2 Hz, 4H);
13C NMR (CDCl3, 75 MHz) δ 51.2, 55.2, 63.1, 75.0, 111.0, 113.8,
118.1, 126.0, 127.0, 128.8, 128.9, 129.9, 132.0, 136.7, 140.9, 160.0;
ESI-MS m/z 308.15 [M + H]+, 330.15 [M + Na]+.Anal. Calcd
for C18H17N3O2 C, 70.34; H, 5.58; N, 13.67. Found: C, 70.28; H,
5.67; N, 13.61.
Supporting Information Available: Experimental procedure,
compound characterization, crystallographic data of compounds
1
of 3d and 5b, and copies of H and 13C NMR spectra of all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO900428J
J. Org. Chem. Vol. 74, No. 9, 2009 3615