Fused polycyclic compounds via Cycloaddition of 4-(1′-Cyclohexenyl)- 5-iodo-1,2,3-triazoles with 4-phenyl-1,2,4-triazoline-3,5-dione: The importance of a sacrificial iodide leaving group

Article abstract of DOI:10.1021/jo400271j

4-(1′-Cyclohexenyl)-5-iodo-1,2,3-triazole and 4-phenyl-1,2,4- triazoline-3,5-dione undergo a formal Diels-Alder reaction, which following an S_N2′ solvolysis process to displace the iodo group affords a fused polycyclic compound.

Full text of DOI:10.1021/jo400271j

Note
pubs.acs.org/joc
Fused Polycyclic Compounds via Cycloaddition of 4‑(1′-
Cyclohexenyl)-5-iodo-1,2,3-triazoles with 4‑Phenyl-1,2,4-triazoline-
3,5-dione: The Importance of a Sacrificial Iodide Leaving Group
Heather A. Michaels,† J. Tyler Simmons, Ronald J. Clark, and Lei Zhu*
Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee, Florida 32306-4390, United
States
S
* Supporting Information
ABSTRACT: 4-(1′-Cyclohexenyl)-5-iodo-1,2,3-triazole and 4-
phenyl-1,2,4-triazoline-3,5-dione undergo a formal Diels−Alder
reaction, which following an SN2′ solvolysis process to displace
the iodo group affords a fused polycyclic compound.
1,2,3-Triazoles are increasingly valuable compounds in the areas
of medicinal and bioconjugate chemistry because of their ease
of synthesis, chemical stability, and potential biological
activities.1 As an example of the potential of 1,2,3-triazoles as
pharmaceuticals, the combinatorial drug Zosyn (Chart 1)
Scheme 1. Known Reactions Mentioned in the Text: (A)
Copper(I)-Catalyzed Azide−Alkyne Cycloaddition;2,3 (B)
Ruthenium(II)-Catalyzed Azide−Alkyne Cycloaddition;4
(C) Hetero-Diels−Alder Reaction of 4-Alkenylthiazole and
1,2,4-Triazoline-3,5-dione;18 and (D) 5-Iodo-1,2,3-triazole
Formation from Azide and Alkyne9
Chart 1. Zosyn
marketed by Pfizer has a 1,2,3-triazolyl-containing component.
The current synthetic methods offer rapid access to both 1,4-
and 1,5-disubstituted 1,2,3-triazoles from copper(I)- or
ruthenium(II)-mediated azide−alkyne cycloadditions (Schemes
1A and 1B, respectively) with broad substrate scopes.2−4 In
comparison, the regioselective preparation of 1,4,5-trisubsti-
tuted-1,2,3-triazoles, which would further enhance the func-
tional versatility of 1,2,3-triazolyl-containing substances, is
relatively underdeveloped. Several methods for preparing 5-
iodo-1,2,3-triazoles, which can be further elaborated using
palladium-catalyzed cross-coupling reactions, are available.5−9
The de novo synthesis of 1,4,5-trisubstituted 1,2,3-triazoles via
an amine-catalyzed reaction between a ketone and an aromatic
azide was recently reported.10−12 Another strategy is post-
synthetic functionalization of the C5 position of 1,4-
disubstituted 1,2,3-triazoles via transition metal-mediated
processes.13−17
Received: February 7, 2013
© XXXX American Chemical Society
A
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a
Scheme 2. Postulated Mechanisms of the Reaction between 1T and PTAD
a
Ph = phenyl. Paths A and A′, proton transfer; paths B and C, solvolysis (1B, R = H; 1C, R = CH3) of the PI intermediate; paths D and D′, indirect
and direct formation of the Diels−Alder intermediate 1D. Path A′ from PI and/or 1,5-H shift from 1D affords the major product 1.
The reaction of a 4-alkenylthiazole with 4-phenyl-1,2,4-
triazoline-3,5-dione (PTAD)19 was reported to afford a
polyheterocyclic compound through a concerted Diels−Alder
(D−A) pathway (Scheme 1C).18 The structural similarity
between thiazole and 1,2,3-triazole led us to hypothesize that 4-
alkenyl-1,2,3-triazoles may also undergo D−A reactions with
dienophiles, resulting in fused heterocycles via functionalization
of the C5 position with a 100% atom economy.
However, 4-(1′-cyclohexenyl)-1,2,3-triazoles react with
PTAD in THF at room temperature to afford primarily the
ene reaction products,20 as is typically observed in reactions
between an alkene and PTAD.21 The details of the reaction
between 1,2,3-triazole 1T and PTAD are illustrated in Scheme
2. In addition to the ene product 1, compound 1A was
observed as a minor side product.22 If water was not carefully
excluded, the water adduct 1B was also observed. When water
was intentionally added to the reaction mixture in CH3CN up
to 25%, the amount of water adduct 1B as a mixture of two
diastereomers rose to 34% (Figure S1 in Supporting
Information). The reaction conducted in CH3OH affords the
CH3OH adduct 1C, also as a mixture of two diastereomers.
The structure of the major diastereomer 1C was confirmed via
single crystal X-ray crystallography (Figure 1).23
arene may involve a zwitterionic intermediate.24−28 As
proposed in Scheme 2, following the addition of PTAD to
1T, the zwitterionic intermediate PI containing a benzylic-like
cation may undergo proton transfer (paths A and A′) to afford
enamide 1A and major product 1,29 or solvolysis to give 1B or
1C in a mixture of diastereomers. In addition to these
pathways, the PI may choose ring closure to give the formal
Diels−Alder product 1D, which tautomerizes to the major ene
reaction product 1 or undergoes stereospecific SN2′ solvolysis
due to the propensity of the urazolyl as a leaving group to give
1B or 1C as single diastereomers.
Alternatively, as suggested by a reviewer, the D−A product
1D may form first from 1T and PTAD via path D′ (Scheme 2).
Intermediate 1D may equilibrate with the zwitterionic
intermediate PI, which provides pathways to reach 1A and
1B/1C as mixtures of diastereomers. The 1,5-hydride shift
pathway is available to 1D to afford the major product 1. In
contrast to the pathway described in the previous paragraph, in
which the formation of PI precedes the D−A intermediate 1D,
the alternative pathway has the D−A intermediate formation
first, which then subsequently transforms to the PI
intermediate in a reversible reaction (path D). The reaction
between 1T and PTAD in methanol results in predominantly
one diastereomer (84%, Figures S2 and S3 in the Supporting
Information), of which the triazolyl and urazolyl groups are cis
to each other (Figure 1). This observation supports the
mechanism involving the initial formation of D−A intermediate
1D, which rapidly undergoes the stereospecific SN2′ meth-
anolysis to afford diastereomer 1C shown in Figure 1. The
minor diastereomer can be attributed to the SN1 methanolysis
from the PI intermediate produced via the reversible path D
(Scheme 2).
The observation of the solvent adducts 1B and 1C in
diastereomeric mixtures leads to the formulation of a stepwise
mechanism involving a polar intermediate (PI in Scheme 2).
The electrophilic addition of PTAD to an alkene, a diene, or an
The intermediary of the formal D−A product 1D is
1
supported by the H NMR time-course experiment (Figure
2). Compound 1T (1H NMR spectrum in THF-d8 is shown in
Figure S6 in the Supporting Information) reacts rapidly with
PTAD in THF-d8 to afford 1D within the time required to
1
acquire the first H NMR spectrum after the initial mixing, ca.
Figure 1. (A) ChemDraw and (B) ORTEP views of the major
diastereomer of compound 1C (30% ellipsoids). Hydrogen and
carbon, black; nitrogen, blue; oxygen, red.
75 s. The two doublets at 5.42 and 5.27 ppm (Figure 2) are
assigned to the diastereotopic HK of the D−A intermediate 1D
B
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Note
Scheme 3. Reaction of 5-Iodo-1,2,3-triazole 2T with PTAD
a
in THF To Afford 2
1
Figure 2. Benzylic proton regions of H NMR spectra (500 MHz,
a
Benzylic protons X, Y, and Z are marked in Figure 3. The addition of
AgNO3 may aid the elimination of iodide in the bottom route to reach
the cationic intermediate.
THF-d8) of the reaction of 1T (0.05 mmol) with PTAD (0.05 mmol)
over the first 10 min, after which no apparent change of the spectrum
was observed. Peak assignments (K, L, M, N) are shown in Scheme 2.
The Supporting Information contains an expansion (Figure S4) and
additional peak assignments (Figure S5).
(Scheme 2). The two doublets subsequently convert to a new
AB spin system slightly downfield that are assigned to the
benzylic HL (5.55 and 5.53 ppm) of the isolated ene product 1.
The minor product 1A, of which the singlet benzylic HM (5.50
ppm) is shown in Figure 2, appears simultaneously with
intermediate 1D. The formation of the zwitterionic inter-
mediate PI, which is the precursor of 1A, is therefore very rapid
either directly from 1T and PTAD or from 1D via a fast
equilibrium. At this moment, we are not able to distinguish
these two scenarios. The hydrolyzed side product 1B has a
delayed appearance (benzylic HN in Figure 2), which suggests
that in addition to the direct hydroxylation of the zwitterionic
intermediate PI, nucleophilic attack of water at C* in 1D
(Scheme 2) displaces the urazolyl group at the C5 position of
the triazole ring via an SN2′ pathway.
We concluded on the basis of the above data that contrary to
our initial intention of a D−A type reaction, the reaction
between 4-(1′-cyclohexenyl)-1,2,3-triazole and PTAD is
unsuccessful in functionalizing the C5 position of a 1,2,3-
triazole. The mechanistic information revealed in these
experiments, however, led to the formulation of a new strategy
for achieving our original objective. In Scheme 2, solvolysis of
the D−A intermediate 1D results in the opening of the six-
membered ring because of the propensity of the urazolyl
moiety as a leaving group. A surrogate leaving group
preinstalled at the C5 position may also facilitate the solvolysis
but would retain the polycyclic core of 1D, hence the
functionalization at the C5 position.
Figure 3. 1H NMR spectra (500 MHz, THF-d8) of the reaction
between 2T (0.04 mmol) and PTAD (0.05 mmol) over the first 10
min at 5 °C. The reaction did not reach completion when the
experiment was terminated. X, Y, and Z are marked in Scheme 3. 2T,
blue; 2D, green; 2, red.
in Figure 3), which was characterized via single crystal X-ray
crystallography (Figure 4). Hydrolysis of 2D occurs either via a
concerted SN2′ pathway or following the formation of a cationic
The 5-iodo-1,2,3-triazole 2T (Scheme 3) was prepared via a
recently reported method, in which mixing Cu(ClO4)2·6H2O
and NaI or KI produces copper(I) catalyst and triiodide
electrophile to collectively mediate the one-step 5-iodo-1,2,3-
triazole formation from an alkyne and an azide (Scheme 1D).9
In the reactions affording 2T−11T, an accelerating ligand
TBTA30,31 was required.9 The reaction of 2T with PTAD was
monitored via 1H NMR spectroscopy. Similar to 1T, the
reaction initially affords the D−A product (2D, Scheme 3),
which was observed in the spectra collected during the early
stage of the reaction at 5 °C (green in Figure 3). 2D
subsequently transforms into the more stable compound 2 (red
Figure 4. (A) ChemDraw and (B) ORTEP views of compound 2
(30% ellipsoids). Hydrogen and carbon, black; nitrogen, blue; oxygen,
red.
C
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Note
intermediate after eliminating the iodide, especially when
assisted by AgNO3 (Scheme 3). Therefore, different from 1T,
instead of the urazolyl group, iodide from 2T is displaced from
either route to afford the fused polycyclic compound 2
(Scheme 3).
Table 1. Structures and Isolated Yields of 4-(1′-
Cyclohexenyl)-5-iodo-1,2,3-triazoles and Major Products of
the Subsequent Reactions with PTAD
A few other 4-(1′-cyclohexenyl)-5-iodo-1,2,3-triazoles were
subjected to this procedure to afford fused tetracyclic products
in modest to good yields (Table 1). AgNO3 is not required, but
it may increase the yield presumably by aiding the departure of
the iodo group or by scavenging the formed iodide. The
addition of water (Figure S7 in the Supporting Information) to
the reaction mixture hampers the reaction by consuming
PTAD. 5-Iodo-1,2,3-triazoles (e.g., 2T) appear to have a lower
reactivity than 5-proto-1,2,3-triazoles (e.g., 1T) toward PTAD.
The side reactions between other nucleophiles in the reaction
system and PTAD consequently become significant, leading to
the moderate isolated yields in many cases.
In conclusion, we have demonstrated that the C5 position of
a 4-(1′-cyclohexenyl)-5-iodo-1,2,3-triazole can be further
functionalized via a reaction with PTAD to afford a
polyheterocyclic structure. The appearance of a zwitterionic
intermediate in the reaction mechanism is supported by the
analysis of product distributions. A formal Diels−Alder
1
intermediate was observed using H NMR spectroscopy, the
formation of which either precedes or follows the formation of
the zwitterionic intermediate. Subsequent SN2′ solvolysis of the
Diels−Alder intermediate leads to the formation of polycyclic
compounds at the expense of the iodide as the leaving group.
Without the 5-iodo group, a more typical ene reaction product
is afforded without functionalization at the C5 position.
EXPERIMENTAL SECTION
■
Warning! Low-molecular-weight organic azides and copper(II) per-
chlorate used in this study are potentially explosive. Appropriate protective
measures should always be taken when handling these compounds.
Solvents and reagents were purchased from various commercial
sources and were used without further purification. Cu(ClO4)2·6H2O
was placed in a vacuum oven at 40 °C for 16 h and was stored in a dry
keeper before use. 1H NMR kinetic experiments were conducted on a
500 MHz NMR spectrometer. Characterizations of new compounds
were performed on 300 or 500 MHz NMR spectrometers. CDCl3 was
treated with alumina gel before use. All chemical shifts are reported in
δ units relative to tetramethylsilane. Flash chromatography was
performed using alumina (80−200 mesh) or silica gel as the stationary
phase. The organic azides were prepared using known procedures.32,33
The acceleratory ligand tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-
amine (TBTA) was prepared according to a published procedure.31
Compounds 1, 1A, and 1B. Compound 1T (121 mg, 0.506
mmol) was added to a 5 mL flame-dried round-bottom flask equipped
with a stir bar. PTAD (94 mg, 0.54 mmol) was added to the flask,
which was then sealed with a septum. Dry THF (2.5 mL) was added
via a syringe, and the reaction mixture was allowed to stir at rt. The
indicative red color of PTAD faded within 4 min to a pale pink, and
after 9 min the pink color disappeared. The two products (1 and 1A)
were separated on a silica column eluted with ethyl acetate in CH2Cl2
(0−50%) to afford the major product 1 in 31% yield as an amorphous
solid (64 mg, 0.15 mmol). The minor product 1A was isolated in <5%
yield as an amorphous solid.
Major Product 1. 1H NMR (500 MHz, CDCl3): δ 8.66 (s(b), 1H),
7.51 (s, 1H), 7.50 (d, J = 4.4 Hz, 4H), 7.41 (t, J = 4.3 Hz, 1H), 7.38 (d,
J = 2.0 Hz, 1H), 7.37 (d, J = 1.8 Hz, 2H), 7.29−7.27 (m, 2H), 6.84 (td,
J = 2.4, 1.5 Hz, 1H), 5.55 (d, J = 15 Hz, 1H), 5.48 (d, J = 15 Hz, 1H),
5.13 (m, 1H), 2.31−2.21 (m, 2H), 2.18−2.12 (m, 1H), 2.12−2.04 (m,
1H), 2.01−1.92 (m, 1H), 1.83−1.66 (m, 3H). 13C NMR (125 MHz,
CDCl3): δ 153.1 (q), 152.4 (quaternary), 146.3 (quaternary), 134.5
(CH), 133.8 (quaternary), 131.5 (quaternary), 129.2 (CH), 129.1
a
1-Ethynylcyclohexene (5 mmol), azide (5 mmol), THF (50 mL),
TEA (5 mmol), NaI (20 mmol), TBTA (0.3 mmol), and
Cu(ClO4)2·6H2O (10 mmol), rt. 5-Iodo-1,2,3-triazole (0.5 mmol),
THF (2.5 mL), and PTAD (0.55 mmol), rt. AgNO3 (0.5 mmol) assists
the reaction in several cases.
b
D
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Note
(CH), 128.8 (CH), 128.0 (CH), 128.0 (CH), 125.4 (CH), 123.9
(quaternary), 119.7 (CH), 54.2 (CH2), 52.0 (CH), 26.9 (CH2), 24.9
(CH2), 19.3 (CH2). HRMS (EI, double-focusing): m/z [M+] calcd for
C23H22N6O2 414.1804, found 414.1796.
Hz, 2H), 2.60−2.49 (m, 2H), 1.81−1.65 (m, 4H). 13C NMR (125
MHz, CD3CN): δ 158.2, 129.5, 128.4, 128.1, 121.3, 117.2, 114.6, 77.1,
66.3, 49.8, 27.1, 25.0, 22.4, 21.7. HRMS (ESI-TOF): m/z [M + H]+
calcd for C16H19N3IO 396.05728, found 396.05655.
Compound 5T. Representative procedure in 52% yield as an
amorphous solid (246 mg, 0.64 mmol). 1H NMR (500 MHz, CDCl3):
δ 6.46 (m, 1H), 4.42−4.39 (m, 2H), 2.61−2.56 (m, 2H), 2.29−2.23
(m, 2H), 1.97−1.90 (m, 2H), 1.85−1.79 (m, 2H), 1.75−1.69 (m, 3H),
1.43−1.26 (m, 9H), 0.92 (t, J = 6.8 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ 151.1, 128.4, 128.2, 74.6, 50.7, 31.7, 29.9, 29.1, 29.0, 27.3,
26.4, 25.4, 22.7, 22.6, 22.0, 14.1. HRMS (EI, double-focusing): m/z
[M]+ calcd for C16H27IN3 388.1250, found 388.1257.
Compound 6T. Representative procedure in 60% yield as an
amorphous solid (288 mg, 0.69 mmol). 1H NMR (500 MHz, DMSO-
d6): δ 8.40 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.95 (d, J =
8.5 Hz, 1H), 7.78 (td, J = 5.4, 1.5 Hz, 1H), 7.62 (td, J = 5.8, 1.2 Hz,
1H), 7.19 (d, J = 8.5 Hz, 1H), 6.49 (pent, J = 1.9 Hz, 1H), 5.97 (s,
2H), 2.54−2.49 (m, 2H), 2.23−2.17 (m, 2H), 1.76−1.70 (m, 2H),
1.66−1.60 (m, 2H). 13C NMR (125 MHz, DMSO-d6): δ 155.7, 150.6,
147.4, 137.9, 130.5, 129.1, 128.6, 128.4, 127.5, 127.3, 127.2, 119.7,
80.9, 55.9, 27.3, 25.3, 22.7, 22.0. HRMS (CI, double-focusing,
isobutane reagent gas): m/z [M + H]+ calcd for C18H18IN4
417.0576, found 417.0586.
Compound 7T. Representative procedure in 81% yield as an
amorphous solid (317 mg, 0.71 mmol). 1H NMR (500 MHz, DMSO-
d6): δ 7.59 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 6.44 (pent, J =
1.8 Hz, 1H), 2.49−2.44 (m, 2H), 2.21−2.16 (m, 2H), 1.74−1.70 (m,
2H), 1.65−1.58 (m, 2H). 13C NMR (125 MHz, DMSO-d6): δ 150.7,
135.4, 132.2, 130.0, 128.5, 127.5, 121.6, 80.1, 53.1, 27.3, 25.3, 22.7,
22.0. HRMS (CI, double-focusing, isobutane reagent gas): m/z [M +
H]+ calcd for C15H16BrN3I 443.9572, found 443.9580.
1
Minor Product 1A. H NMR (500 MHz, CDCl3): δ 9.69 (s(b),
1H), 7.59−7.45 (m, 5H), 7.44−7.35 (m, 4H), 7.33−7.24 (m, 2H),
5.51 (s, 2H), 2.47 (s, 2H), 2.58 (s, 2H), 1.90−1.70 (m, 4H). 13C NMR
(125 MHz, CDCl3): δ 154.5 (quaternary), 151.5 (quaternary), 146.0
(quaternary), 134.2 (quaternary), 131.5 (quaternary), 129.3 (CH),
129.1 (CH), 129.0 (CH), 128.8 (quaternary), 128.1 (CH), 128.0
(quaternary), 125.6 (CH), 121.9 (CH), 54.3 (CH2), 29.2 (CH2), 25.6
(CH2), 22.2 (CH2), 21.8 (CH2). HRMS (EI, double-focusing): m/z
[M+] calcd for C23H22N6O2 414.1804, found 414.1804.
Minor Product 1B from Hydrolysis. 1H NMR (500 MHz, CDCl3):
δ 8.47 (s(b), 1H), 7.67 (s, 1H), 7.52−7.45 (m, 4H), 7.39 (m, 5H),
7.30 (m, 1H), 5.54 (d, J = 14.8 Hz, 2H), 4.90 (s(b), 1H), 4.50 (dd, J =
8.1, 4.3 Hz, 1H), 2.30 (m, 1H), 2.05 (m, 1H), 1.95 (m, 2H), 1.81 (m,
2H), 1.52 (m, 1H), 1.13 (m, 1H). HRMS (EI, double-focusing): m/z
[M+] calcd for C23H24N6O3 432.1910, found 432.1905.
Preparative Synthesis of 1C. Compound 1T (120 mg, 0.501
mmol) was added to a flame-dried 10 mL round-bottom flask
equipped with a stir bar. PTAD (95 mg, 0.54 mmol) was added as a
solid, and the flask was sealed with a septum. CH3OH (2.5 mL) was
added via a syringe. Within 15 min of mixing, the red color of PTAD
disappeared and the reaction was stopped via dilution with CH2Cl2 (3
mL). Upon solvent removal, the reaction mixture was separated on a
silica column eluted with ethyl acetate in CH2Cl2 (0−100%). The
CH3OH adduct (1C) was isolated in <10% yield as an amorphous
1
solid. H NMR (500 MHz, CDCl3): δ 10.40 (s, 1H), 7.58 (d, J = 7.9
Hz, 2H), 7.57 (s, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.45 (d, J = 6.2 Hz,
2H), 7.39 (tt, J = 4.8, 1.2 Hz, 1H), 7.34−7.31 (m, 2H), 5.66 (d, J =
14.9 Hz, 1H), 5.59 (d, J = 13.9 Hz, 1H), 4.66 (dd, J = 8.4, 4.0 Hz, 1H),
3.23 (s, 3H), 2.29 (d, J = 14.6 Hz, 1H), 2.05 (qd, J = 8.0, 3.6 Hz, 1H),
1.99 (m, 1H), 1.84 (d, J = 12.4 Hz, 1H), 1.78 (d, J = 12.4 Hz, 1H),
1.52 (qt, J = 5.1, 4.4 Hz, 1H), 1.13 (qt, J = 5.6, 3.6 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 153.1, 152.8, 147.4, 134.0, 131.8, 129.4, 129.1,
129.05, 128.1, 127.9, 125.7, 123.8, 61.0, 54.6, 50.5, 41.0, 35.7, 28.1,
25.4, 22.9. HRMS (ESI-TOF): m/z [M + H+] calcd for C24H27O3N6
447.2145, found 447.2145.
Compound 8T. Representative procedure in 42% yield as an
amorphous solid (157 mg, 0.42 mmol). 1H NMR (500 MHz, DMSO-
d6): δ 8.15 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.6 Hz, 2H), 6.50 (s, 1H),
2.55−2.49 (m, 2H), 2.27−2.21 (m, 2H), 1.79−1.72 (m, 2H), 1.69−
1.62 (m, 2H). 13C NMR (125 MHz, DMSO-d6): δ 151.4, 140.8, 134.2,
128.6, 128.2, 128.1, 118.4, 113.4, 81.4, 27.5, 25.4, 22.7, 22.0. HRMS
(CI, double-focusing, isobutane reagent gas): m/z [M + H]+ calcd for
C15H14IN4 377.0263, found 377.0270.
Compound 2T. This is a representative procedure for preparing
2T−11T. Benzylazide (676.1 mg, 5.08 mmol) and 1-ethynylcyclohex-
ene (547.0 mg, 5.15 mmol) were dissolved in THF (50 mL) in a 100
mL round-bottom flask equipped with a stir bar. Triethylamine (520
mg, 5.14 mmol) was added, followed by NaI (3.2 g, 21 mmol). The
mixture was allowed to stir at rt for ∼5 min before a catalytic amount
of TBTA (174 mg, 0.33 mmol) and Cu(ClO4)2·6H2O (3.75 g, 10.1
mmol) were added sequentially. The reaction mixture was stirred at rt
for an additional 18 h before it was diluted with ethyl acetate and 10%
NH4OH solution and transferred to a separatory funnel. The product
was extracted with ethyl acetate (30 mL × 3), washed with saturated
brine, and dried over Na2SO4. Upon solvent removal, compound 2T34
was isolated on an alumina column eluted with CH2Cl2 in hexanes (0−
Compound 9T. Representative procedure in 64% yield as an
amorphous solid (127 mg, 0.30 mmol). 1H NMR (300 MHz, CDCl3):
δ 7.70 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 6.52−6.46 (m,
1H), 2.63−2.55 (m, 2H), 2.30−2.21 (m, 2H), 1.87−1.66 (m, 4H). 13C
NMR (125 MHz, DMSO-d6): δ 151.0, 136.6, 132.9, 129.2, 128.3,
128.2, 123.8, 81.7, 27.4, 25.4, 22.7, 22.0. HRMS (CI, double-focusing,
isobutane reagent gas): m/z [M + H]+ calcd for C14H14N3BrI
429.9416, found 429.9415.
Compound 10T. Representative procedure in 50% yield as an
amorphous solid (227 mg, 0.58 mmol). 1H NMR (500 MHz, DMSO-
d6): δ 7.50 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 6.50 (s, 1H),
3.04 (pent, J = 6.9 Hz, 1H), 2.57−2.48 (m, 2H), 2.27−2.18 (m, 2H),
1.79−1.70 (m, 2H), 1.70−1.62 (m, 2H), 1.28 (d, J = 6.9 Hz, 6H). 13C
NMR (125 MHz, DMSO-d6): δ 151.0, 150.7, 135.2, 128.4, 128.0,
127.7, 127.0, 81.9, 33.7, 27.4, 25.3, 24.2, 22.7, 22.0. HRMS (CI,
double-focusing, isobutane reagent gas): m/z [M + H]+ calcd for
C17H21IN3 394.0780, found 394.0792.
Compound 11T. Representative procedure in 67% yield as an
amorphous solid (282 mg, 0.74 mmol). 1H NMR (500 MHz, CDCl3):
δ 7.44 (d, J = 8.9 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 6.54 (sept, J = 1.8
Hz, 1H), 2.68−2.62 (m, 2H), 2.33−2.27 (m, 2H), 1.89−1.82 (m, 2H),
1.79−1.72 (m, 2H). 13C NMR (125 MHz, DMSO-d6): δ 160.7, 150.5,
130.3, 128.6, 128.5, 127.9, 114.9, 82.2, 56.1, 27.4, 25.4, 22.7, 22.0.
HRMS (CI, double-focusing, isobutane reagent gas): m/z [M + H]+
calcd for C15H17OIN3 382.0417, found 382.0429.
Compound 2. This is a representative procedure for preparing 2−
11 from 2T−11T, respectively. Compound 2T (184.2 mg, 0.50
mmol), AgNO3 (85.1 mg, 0.50 mmol), and dry THF (2 mL) were
added to a 5 mL flame-dried round-bottom flask equipped with a stir
bar, and the flask was sealed with a septum. PTAD (95.9 mg, 0.55
mmol) was weighed into a separate container and dissolved with dry
1
75%) in 57% yield as an amorphous solid (1.04 g, 2.9 mmol). H
NMR (500 MHz, CDCl3): δ 7.38 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 1.6
Hz, 1H), 7.30 (d, J = 5.7 Hz, 2H), 6.49 (sept, 1H), 5.65 (s, 2H), 2.62−
2.58 (m, 2H), 2.28−2.24 (m, 2H), 1.84−1.79 (m, 2H), 1.74−1.69 (m,
2H).
Compound 3T. Representative procedure in 59% yield as an
amorphous solid (215 mg, 0.59 mmol). 1H NMR (500 MHz,
CD3CN): δ 8.56 (s, 1H), 7.77 (td, J = 6.0, 1.7 Hz, 1H), 7.33 (t, J = 6.4
Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.48 (m, 1H), 5.72 (s, 2H), 2.59−
2.53 (m, 2H), 2.29−2.22 (m, 2H), 1.84−1.80 (m, 2H), 1.74−1.68 (m,
2H). 13C NMR (125 MHz, CD3CN): δ 154.8, 151.2, 149.5, 137.1,
128.4, 128.0, 123.1, 121.7, 76.9, 27.1, 25.0, 22.5, 21.7. HRMS (CI,
double-focusing, isobutane reagent gas): m/z [M + H]+ calcd for
C14H16N4I 367.0420, found 367.0433.
Compound 4T. Representative procedure (KI in place of NaI) in
63% yield as an amorphous solid (50 mg, 0.13 mmol). 1H NMR (300
MHz, CDCl3): δ 7.30−7.24 (m, 2H), 6.96 (t, J = 7.3 Hz, 1H), 6.88 (d,
J = 8.0 Hz, 2H), 6.42 (m, 1H), 4.79 (t, J = 5.5 Hz, 2H), 4.41 (t, J = 5.5
E
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Note
THF (0.5 mL). The PTAD solution was then added dropwise via a
syringe to the reaction flask over ∼45 min at a rate such that the red
color had completely vanished between drops. The reaction mixture
was allowed to stir for an additional 60 min at rt before it was diluted
with CH2Cl2 and filtered through a small plug of silica gel to remove
the inorganic materials. The crude product was purified on a silica
column on which the less polar impurities were removed with an
isocratic portion of CH2Cl2. The product was recovered via elution of
20−25% ethyl acetate in CH2Cl2 in 47% yield as an amorphous solid
148.8 (quaternary), 147.7 (quaternary), 147.5 (quaternary), 137.1
(CH), 132.8 (quaternary), 130.9 (quaternary), 130.5 (quaternary),
129.9 (CH), 129.2 (CH), 128.9 (CH), 128.6 (CH), 127.8 (CH),
127.5 (quaternary), 126.7 (CH), 125.8 (CH), 118.7 (CH), 68.5
(quaternary), 59.6 (CH), 55.8 (CH2), 35.2 (CH2), 27.8 (CH2), 24.2
(CH2), 22.7 (CH2). HRMS (ESI-TOF): m/z [M + H]+ calcd for
C26H24N7O3 482.1941, found 482.1955.
Compound 7. Representative procedure in 53% yield as an
amorphous solid (134 mg, 0.26 mmol). AgNO3 was not used in this
case. 1H NMR (500 MHz, CDCl3): δ 7.54−7.43 (m, 7H), 7.17 (d, J =
6.4 Hz, 2H), 6.17 (d, J = 5.1 Hz, 1H), 5.94 (d, J = 5.1 Hz, 1H), 4.52
(dd, J = 7.4, 5.0 Hz, 1H), 3.69 (s, 1H), 3.06 (d, J = 3.1 Hz, 1H), 1.93−
1.67 (m, 4H), 1.40 (q, J = 13.5 Hz, 1H), 1.12 (q, J = 13.6 Hz, 1H),
0.88 (q, J = 12.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 148.9
(quaternary), 148.1 (quaternary), 133.8 (quaternary), 133.1 (quater-
nary), 132.0 (CH), 130.4 (quaternary), 129.6 (CH), 129.4 (CH),
129.2 (quaternary), 128.9 (CH), 125.8 (CH), 125.6 (quaternary),
122.6 (quaternary), 68.4 (quaternary), 59.3 (CH), 53.7 (CH2), 35.0
(CH2), 27.9 (CH2), 24.0 (CH2), 22.6 (CH2). HRMS (EI, double-
focusing): m/z [M]+ calcd for C23H21O3BrN6 508.0859, found
508.0846.
Compound 8. Representative procedure in 51% yield as an
amorphous solid (113 mg, 0.26 mmol). AgNO3 was not used in this
case. 1H NMR (500 MHz, CDCl3): δ 7.76 (d, J = 6.4 Hz, 2H), 7.73 (d,
J = 8.9 Hz, 2H), 7.41−7.37 (m, 2H), 7.36−7.32 (m, 3H), 4.61 (dd, J =
7.5, 4.9 Hz, 1H), 4.02 (d, J = 4.9 Hz, 1H), 2.05−2.01 (m, 1H), 1.84−
1.70 (m, 3H), 1.46−1.35 (m, 1H), 1.28−1.11 (m, 2H). 13C NMR
(125 MHz, CDCl3): δ 149.3 (quaternary), 148.6 (quaternary), 140.1
(quaternary), 133.2 (quaternary), 133.1 (CH), 130.2 (quaternary),
129.7 (quaternary), 129.4 (CH), 129.0 (CH), 125.7 (CH), 124.6
(CH), 117.8 (quaternary), 113.3 (quaternary), 68.8 (quaternary), 59.4
(CH), 34.9 (CH2), 28.6 (CH2), 24.1 (CH2), 22.5 (CH2). HRMS
(ESI-TOF): m/z [M + H]+ calcd for C23H19N7O3 442.1628, found
442.1633.
Compound 9. Representative procedure in 44% yield as an
amorphous solid (39 mg, 0.08 mmol). AgNO3 was not used in this
case. 1H NMR (300 MHz, CDCl3): δ 7.65 (d, J = 8.7 Hz, 2H), 7.48 (d,
J = 8.7 Hz, 2H), 7.45−7.33 (m, 5H), 4.67 (dd, J = 12, 6.0 Hz, 1H),
3.15 (d, J = 12 Hz, 1H), 2.63 (s, 1H), 1.92−1.76 (m, 4H), 1.53−1.43
(m, 1H), 1.32−1.20 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 149.4
(quaternary), 148.4 (quaternary), 135.9 (quaternary), 133.0 (quater-
nary), 132.3 (CH), 130.3 (quaternary), 129.7 (quaternary), 129.3
(CH), 128.9 (CH), 125.8 (CH), 125.7 (CH), 123.7 (quaternary), 68.8
(quaternary), 59.5 (CH), 35.0 (CH2), 28.5 (CH2), 24.2 (CH2), 22.6
(CH2). HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H20BrN6O3
495.0780, found 495.0781.
1
(100.3 mg, 0.233 mmol). H NMR (500 MHz, CDCl3): δ 7.54 (m,
4H), 7.46 (m, 3H), 7.31 (m, 3H), 6.26 (d, J = 15.4 Hz, 1H), 6.05 (d, J
= 14.6 Hz, 1H), 4.55 (dd, J = 7.1, 5.4 Hz, 1H), 3.11 (d, J = 13.4 Hz,
1H), 3.00 (s, 1H), 1.93−1.70 (m, 4H), 1.43 (qt, J = 6.8, 3.8 Hz, 1H),
1.81 (qt, J = 6.8, 3.8 Hz, 1H), 0.92 (qd, J = 9.8, 3.8 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 149.0 (quaternary), 148.1 (quaternary), 134.8
(quaternary), 133.0 (quaternary), 130.5 (quaternary), 129.4 (CH),
129.3 (CH), 128.9 (CH), 128.4 (CH), 127.7 (CH), 125.8 (CH), 68.4
(CH), 59.3 (CH2), 54.3 (CH2), 35.1 (CH2), 27.9 (CH2), 24.0 (CH2),
22.6 (CH2). HRMS (EI, double-focusing): m/z [M]+ calcd for
C23H22N6O3 430.1754, found 430.1756.
Compound 3. Representative procedure in 55% yield as an
amorphous solid (120.1 mg, 0.278 mmol). 1H NMR (500 MHz,
CDCl3): δ 8.46 (d, J = 4.7 Hz, 1H), 7.67 (td, J = 6.0, 1.8 Hz, 1H),
7.47−7.41 (m, 4H), 7.41−7.37 (m, 1H), 7.21 (dd, J = 5.1, 2.6 Hz,
1H), 7.17 (d, J = 7.8 Hz, 1H), 6.38 (d, J = 16.4 Hz, 1H), 6.06 (d, J =
15.8 Hz, 1H), 4.54 (dd, J = 7.4, 5.0 Hz, 1H), 4.28 (s, 1H), 3.06 (d, J =
12.2 Hz, 1H), 1.93 (d, J = 14.5 Hz, 1H), 1.84 (td, J = 8.8, 4.1 Hz, 1H),
1.77−1.69 (m, 2H), 1.41 (qt, J = 12.9, 3.6 Hz, 1H), 1.31−1.12 (m,
2H). 13C NMR (125 MHz, CDCl3): δ 154.5 (quaternary), 149.5
(CH), 149.0 (quaternary), 147.7 (quaternary), 136.9 (CH), 132.8
(quaternary), 130.6 (quaternary), 130.4 (quaternary), 129.3 (CH),
128.7 (CH), 125.8 (CH), 122.9 (CH), 121.4 (CH), 68.3 (quaternary),
59.6 (CH), 55.4 (CH2), 35.0 (CH2), 27.7 (CH2), 24.1 (CH2), 22.6
(CH2). HRMS (EI, double-focusing): m/z [M]+ calcd for C22H21O3N7
431.1706, found 431.1704.
Compound 4. Representative procedure in 67% yield as an
amorphous solid (102 mg, 0.22 mmol). AgNO3 was not used in this
case. 1H NMR (500 MHz, CDCl3): δ 7.52−7.41 (m, 5H), 7.26 (t, J =
7.3 Hz, 2H), 6.97 (t, J = 6.4 Hz, 1H), 6.80 (d, J = 7.8 Hz, 2H), 5.58
(dt, J = 6.3, 2.1 Hz, 1H), 5.04 (dt, J = 5.5, 4.3 Hz, 1H), 4.50 (d, J = 5.2
Hz, 1H), 4.43 (t, J = 4.9 Hz, 2H), 4.13 (s, 1H), 3.00 (d, J = 14.1 Hz,
1H), 1.85 (d, J = 12.3 Hz, 1H), 1.79 (td, J = 8.6, 4.9 Hz, 1H), 1.69 (d,
J = 15.3 Hz, 1H), 1.60 (d, J = 15 Hz, 1H), 1.63 (qt, J = 12.9, 4.9 Hz,
1H), 1.06 (qt, J = 12.9, 4.3 Hz, 1H), 0.92 (qd, J = 9.2, 4.3 Hz, 1H). 13C
NMR (500 MHz, CDCl3): δ 158.0, 148.9, 147.9, 132.5, 130.5, 130.1,
129.6, 129.3, 128.8, 125.8, 121.4, 114.5, 68.3, 66.4, 59.4, 50.6, 34.9,
27.8, 24.0, 22.4. HRMS (EI, double-focusing): m/z [M]+ calcd for
C24H24N6O4 460.1859, found 460.1863.
Compound 5. Representative procedure in 72% yield as an
amorphous solid (164 mg, 0.36 mmol). AgNO3 was not used in this
case. 1H NMR (500 MHz, CDCl3): δ 7.53 (d, J = 4.2 Hz, 4H), 7.46 (t,
J = 4.7 Hz, 1H), 4.99−4.92 (m, 1H), 4.81−4.73 (m, 1H), 4.58 (dd, J =
7.4, 5.0 Hz, 1H), 3.36 (s, 1H), 3.08 (d, J = 15.0 Hz, 1H), 1.90−1.71
(m, 4H), 1.52−1.39 (m, 1H), 1.24−1.05 (m, 2H). 13C NMR (125
MHz, CDCl3): δ 149.2 (quaternary), 148.1 (quaternary), 132.6
(quaternary), 130.6 (quaternary), 129.3 (CH), 129.2 (quaternary),
128.8 (CH), 125.6 (CH), 68.4 (quaternary), 59.5 (CH), 51.5 (CH2),
35.1 (CH2), 31.7 (CH2), 30.0 (CH2), 29.1 (CH2), 29.0 (CH2), 28.0
(CH2), 26.4 (CH2), 24.0 (CH2), 22.7 (CH2), 22.6 (CH2), 14.0 (CH3).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C24H33N6O3 453.2614,
found 453.2601.
Compound 10. Representative procedure in 53% yield as an
amorphous solid (117.5 mg, 0.26 mmol). AgNO3 was not added in
1
this case. H NMR (500 MHz, CDCl3): δ 7.52 (d, J = 8.5 Hz, 2H),
7.44−7.35 (m, 7H), 4.68 (dd, J = 7.6, 4.9 Hz, 1H), 3.91 (s, 1H), 3.10
(d, J = 11.6 Hz, 1H), 3.02 (pent, J = 6.9 Hz, 1H), 2.05 (d, J = 16.2 Hz,
1H), 1.88 (td, J = 9.5, 3.9 Hz, 1H), 1.83−1.75 (m, 2H), 1.53−1.42 (m,
1H), 1.32 (d, J = 7.0 Hz, 6H), 1.30−1.20 (m, 2H). 13C NMR (125
MHz, CDCl3): δ 150.4 (quaternary), 149.6 (quaternary), 148.4
(quaternary), 134.6 (quaternary), 133.0 (quaternary), 130.5 (quater-
nary), 129.6 (quaternary), 129.3 (CH), 128.7 (CH), 127.1 (CH),
125.9 (CH), 124.0 (CH), 68.8 (quaternary), 59.5 (CH), 35.0 (CH2),
33.9 (CH3), 28.6 (CH2), 24.2 (CH2), 23.9 (CH), 23.8 (CH), 22.6
(CH2). HRMS (ESI-TOf): m/z [M + H]+ calcd for C25H27N6O3
459.2145, found 459.2161.
Compound 11. Representative procedure in 50% yield as an
amorphous solid (111 mg, 0.25 mmol). AgNO3 was not used in this
case. 1H NMR (500 MHz, CDCl3): δ 7.50 (d, J = 9.0 Hz, 2H), 7.44−
7.36 (m, 5H), 7.01 (d, J = 9.0 Hz, 2H), 4.67 (dd, J = 7.5, 5.0 Hz, 1H),
3.88 (s, 3H), 3.11 (d, J = 11.8 Hz, 1H), 2.05 (d, J = 10.0 Hz, 1H),
1.93−1.76 (m, 3H), 1.54−1.42 (m, 1H), 1.33−1.21 (m, 2H). 13C
NMR (125 MHz, CDCl3): δ 160.3 (quaternary), 149.5 (quaternary),
148.1 (quaternary), 132.8 (quaternary), 130.4 (quaternary), 129.9
(quaternary), 129.8 (quaternary), 129.3 (CH), 128.7 (CH), 125.9
(CH), 125.8 (CH), 114.2 (CH), 68.7 (quaternary), 59.5 (CH), 55.5
Compound 6. Representative procedure in 65% yield as an
amorphous solid (147 mg, 0.31 mmol). AgNO3 was not used in this
case. 1H NMR (500 MHz, CDCl3): δ 8.15 (d, J = 8.5 Hz, 1H), 7.82 (d,
J = 7.3 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.68 (td, J = 5.5, 1.4 Hz,
1H), 7.55 (td, J = 6.9, 1.2 Hz, 1H), 7.42−7.34 (m, 5H), 7.29 (d, J = 8.5
Hz, 1H), 6.64 (d, J = 16.6 Hz, 1H), 6.19 (d, J = 16.6 Hz, 1H), 4.59
(dd, J = 6.8, 4.5 Hz, 1H), 4.16 (s, 1H), 3.14 (d, J = 14.7 Hz, 1H),
2.02−1.95 (m, 1H), 1.95−1.80 (m, 3H), 1.60−1.44 (m, 2H), 1.38−
1.27 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 154.5 (quaternary),
F
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The Journal of Organic Chemistry
Note
(CH3), 35.0 (CH2), 28.5 (CH2), 24.2 (CH2), 22.6 (CH2). HRMS
(ESI-TOF): m/z [M + H]+ calcd for C23H23N6O4 447.1781, found
447.1796.
(14) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R.
Org. Lett. 2008, 10, 3081−3084.
́
(15) Ackermann, L.; Jeyachandran, R.; Potukuchi, H. K.; Novak, P.;
Representative Procedure of the 1H NMR Time-Course
Experiments. THF-d8 (0.5 mL) was added to an NMR tube
equipped with a mixing bulb and a cap. After the tube had been sealed,
it was immersed in a dewar that contained dry ice and acetone. After
cooling at −78 °C for several minutes, the NMR tube was inserted
into the NMR spectrometer and the solvent was locked and shimmed
upon. The NMR tube was quickly removed and reintroduced to the
−78 °C dewar. Compound 1T (11.3 mg, 0.05 mmol) and PTAD (6.7
mg, 0.05 mmol) were transferred from a 0.5 dram vial to the NMR
tube. The sample was quickly mixed by inversion and reinserted into
the spectrometer. Spectra were recorded every 75 s (Figure 2).
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(22) 1A was observed in reactions in all solvents screened: THF,
ethyl acetate, dioxane, toluene, acetonitrile, methanol, and acetonitrile/
water mixture.
ASSOCIATED CONTENT
* Supporting Information
■
S
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Tetrahedron Lett. 2009, 50, 277−280.
1H and 13C NMR spectra of reported compounds, an expanded
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additional informative 1H NMR spectra of crude reaction
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AUTHOR INFORMATION
Corresponding Author
■
*lzhu@chem.fsu.edu
Present Address
†H.A.M: Torrey Pines Institute for Molecular Studies, 11350
SW Village Parkway, Port St. Lucie, FL 34987-2352.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-1213574). We thank Professors Jiong Yang (Texas
A&M University) and Pinjing Zhao (North Dakota State
University) for insightful discussions.
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