Synthesis, structural analysis, and reaction of 3-Aza-5-[7]orthocyclophyne

Article abstract of DOI:10.1246/cl.130735

A newly synthesized 3-aza-5-[7]orthocyclophyne shows labile planar chirality at ambient temperature. Its halogenation reaction efficiently affords well-functionalized 3-aza-[7]orthocyclophenes with stable planar chirality.

Full text of DOI:10.1246/cl.130735

doi:10.1246/cl.130735
1374
Published on the web November 5, 2013
Synthesis, Structural Analysis, and Reaction of 3-Aza-5-[7]orthocyclophyne
Kazunobu Igawa,1 Takeshi Kawabata,2 Runyan Ni,3 and Katsuhiko Tomooka*1
1Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasuga-koen, Kasuga, Fukuoka 816-8580
2Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552
3Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasuga-koen, Kasuga, Fukuoka 816-8580
(Received August 8, 2013; CL-130735; E-mail: ktomooka@cm.kyushu-u.ac.jp)
A newly synthesized 3-aza-5-[7]orthocyclophyne shows
labile planar chirality at ambient temperature. Its halogenation
reaction efficiently affords well-functionalized 3-aza-[7]ortho-
cyclophenes with stable planar chirality.
Mitsunobu reaction of 6 under high-dilution conditions (0.01 M)
successfully provided the desired orthocyclophyne 1b in good
yield (80%). The thus obtained 1b afforded suitable single
crystals to elucidate their detailed structural features in the solid
state by X-ray crystallographic analysis.9 The analysis shows
that the ansa chain is located outside the plane of the benzene
ring; therefore, 1b possesses planar chirality in the solid state
(Figure 2). Moreover, the alkyne moiety is significantly bent,
with C4-C5-C6 and C5-C6-C7 bond angles of 166 and 164°,
respectively.
Cyclophyne, which is a cyclophane with an alkyne-contain-
ing ansa chain, attracts significant interest in synthetic organic
chemistry, structural organic chemistry, and material chemistry
because of its unique conformational, chemical, and spectro-
scopic properties made possible by deformation and strain in
the alkyne and aromatic ring moieties.1,2 Cope and Fordice’s
synthesis of 5-[7]orthocyclophyne 1a (X = CH2) in 1967 is
regarded as one of the pioneering works on cyclophyne
(Figure 1).3 However, for almost half a century, this class of
compounds did not draw much attention in spite of their highly
strained unique structure.4 Recently, we have reported a novel
3-aza-5-[7]orthocyclophene 2 containing a deformed (E)-alkene
in the ansa chain, showing dynamic planar chirality along with
the unique reactivity of alkene owing to its strained cyclic
structure.5 With regard to the novel azaorthocyclophane chem-
istry, we became interested in 3-aza-5-[7]orthocyclophyne 1b
(X = NTs), a nitrogen congener of 1a, which was expected to
show much labile dynamic chirality compared to that of 2 and the
unique reactivity of alkyne. Furthermore, we expected that 1b
could be employed as a versatile precursor for functionalized 2,
in case the trans-selective functionalization of its alkyne moiety
is possible. Herein, we report on the synthesis, structural analysis,
and unique reactivities of 3-aza-5-[7]orthocyclophyne 1b.
1
The H NMR analysis of 1b in CDCl3 at ambient temper-
ature shows two sets of nonequivalent methylene geminal
O
H
MeO2C
Ts
H
a
c
b
N
N
Ts
3
4
HO
H
MeO2C
MeO2C
d
N
1b
N
Ts
Ts
5
6
Scheme 1. Synthesis of 1b. Reagents and conditions: (a)
dimethyl1-diazo-2-oxopropylphosphonate, K2CO3, MeOH, RT,
67%; (b) n-BuLi, then ClCO2Me, THF, ¹78 °C, 77%; (c)
DIBAL, CH2Cl2, ¹78 °C, quant; (d) DEAD, PPh3, THF, 0 °C,
80%.
For this purpose, an efficient approach to construct a
strained nine-membered skeleton was needed; an intramolecular
Mitsunobu reaction was found to be better suited for this
purpose.6 The requisite precursor 6 was readily synthesized from
our previously reported 35 in three steps: (i) construction of an
alkyne moiety using the Ohira-Bestmann reagent;7 (ii) intro-
duction of a hydroxymethyl moiety at the alkyne terminal by an
acylation; and (iii) reduction (Scheme 1).8 An intramolecular
7
1
6
164 °
5
4
1
166 °
7
Y1
N
6
4
5
5
5
6
6
X
Ts
N
Y2
2
2
G‡ = 15.1 kcal mol–1
at 25 °C
N
Ts
Ts
N
1a: X = CH2
1b: X = NTs
2a: Y1, Y2 = H
2b: Y1= Me, Y2 = H
(R)-1b
(S)-1b
Figure 1. 5-[7]Orthocyclophyne 1 and 3-aza-5-[7]orthocyclo-
phene 2.
Figure 2. Molecular structure and dynamic chirality of 1b.
© 2013 The Chemical Society of Japan www.csj.jp/journals/chem-lett/
Chem. Lett. 2013, 42, 1374-1376

1375
–0.327
Cl
I
O
+0.206
I
–0.040
–0.060
N
Ts
Ts
Ts
N
+0.024
+0.060
I
5
6
N
Ts
N
Ts
a
d
I-C5: 2.85 Å
I-C6: 3.03 Å
(E )-2c
7
1b
1b
i
c
b
H
I
Figure 3. Charge distribution of 1b and its π complex i.
Ts
N
N
I
Cl
(a)
(c)
CD
CD
5000
5000
0
0
(Z )-2e
(E )-2d
–5000
–5000
Scheme 2. Transformation of alkyne moiety of 1b. Reagents
and conditions: (a) I2, MeOH, reflux, 89%; (b) n-Bu4NI, 1,2-
dichloroethane, reflux, 87%; (c) TMSCI, NaI, H2O, CH3CN, RT,
79%; (d) [PPh3AuCl], AgOTf, MeOH-H2O, RT, 94%.
15.0
20.0
15.0
20.0
25.0
Time/min
Time/min
UV
1
UV
6
(b)
(d)
105
105
105
0
104
104
0
4
2
5
protons (at C2, C4, C7, and C8), suggesting that the above-
mentioned chiral conformations are maintained to some extent
even in solution and on the NMR time scale. The thermody-
namic parameters for the racemization of 1b are estimated by the
15.0
20.0
15.0
20.0
25.0
Time/min
Time/min
1
fitting of the dynamic H NMR simulation with the VT-NMR
Figure 4. HPLC analysis of (E)-2c and (E)-2d. Analytical
conditions: (a), (b) sample: (E)-2c, column: CHIRALPAK AD-H
(4.6 © 250 mm), eluent: hexane/EtOH = 1/1, flow rate: 0.5
mL min¹1, detection wavelength: 254 nm; (c), (d) sample: (E)-
2d, column: CHIRALPAK AD-H (4.6 © 250 mm), eluent:
hexane/EtOH = 1/1, flow rate: 0.5 mL min¹1, detection wave-
length: 254 nm.
spectra at 0 to 80 °C in toluene-d8 as ¦H‡ = 15.7 kcal mol¹1 and
¹1 10
¦S‡ = 1.88 cal mol¹1 K
.
This result indicates that 1b shows
significant labile planar chirality at ambient temperature. The
estimated half-lives of the optical activity (t1/2) for 1b at 25 and
¹78 °C are 6 © 10¹3 s and 3.1 h, respectively.
Next, the trans-selective halogenation of alkyne moiety in
1b was studied to synthesize functionalized analogs of 2.
Fortunately, a simple diiodination reaction with I2 in MeOH
successfully provided (E)-2c in good yield (89%), without any
contamination of the (Z)-isomer (Scheme 2).11,12
The thus obtained (E)-2c and (E)-2d with a tetrasubstituted
alkene moiety show stable planar chirality at ambient temper-
ature.23 The existence of isolable enantiomers of these products
in solution was proved by HPLC analysis using a chiral
stationary column equipped with a CD spectropolarimeter. As
shown in Figure 4, both the enantiomers of (E)-2c and (E)-2d
were successfully separated;24 the enantiomeric purity of the
isolated enantiomers did not decrease in hexane solution at
ambient temperature for at least two months.
Furthermore, a similar transformation of 1b with a less
nucleophilic species afforded unique ring contraction products;
for example, the reaction of 1b with NIS and AcOH in
dichloromethane provided an eight-membered enamine 8 (42%)
along with a six-membered allylamide 9 (43%) (Scheme 3).9,25
The most probable mechanism for the production of 8 involves
the formation of an aziridinium intermediate iii from the I+
coordinating intermediate ii (path a in Scheme 3), followed by
Interestingly, the dihalogenation reaction of 1b using n-
Bu4NI in 1,2-dichloroethane afforded C5-iodo-C6-chloro-sub-
stituted (E)-2d with high regioselectivity along with high (E)-
selectivity, in 87% yield.13-15 Similar high regioselectivity was
observed in a protoiodination reaction. The reaction of 1b with
NaI, TMSCl, and water in acetonitrile predominantly afforded
the protoiodination product (Z)-2e in 79% yield.9,16-18 The
observed regioselectivity can be explained by the difference
in electron densities between the alkyne carbons. The natural
population analysis of 1b using DFT calculation shows the
charges ¹0.040 and +0.024 for the C5 and C6 positions,
respectively (Figure 3).19 A similar charge distribution was
observed in a π complex with ICl (i); the charges are computed
as ¹0.060 and +0.060 for the C5 and C6 positions, respectively,
with a shorter atomic distance between I and the C5 carbon
(2.85 ¡) than that between I and the C6 carbon (3.03 ¡).19 Thus,
most probably, the reaction proceeds by an anti-selective
termolecular electrophilic addition (AdE3) mechanism with
¹
its ring-opening reaction with AcO . On the other hand, the
formation of 9 can be explained by the sequential intramolecular
Friedel-Crafts reaction of ii (path b in Scheme 3), followed by a
pyrrolidine-ring-opening reaction and deformylation.26 Further
studies to clarify the scope and limitation of these reactions are
underway.
In summary, a concise synthetic approach to 3-aza-5-
[7]orthocyclophyne 1b is described. The newly synthesized 1b
shows labile planar chirality and high reactivity at the alkyne
¹
regioselective bond formation of I+-anionic-C5 and Cl -cation-
ic-C6.20,21 Similarly, the Lewis acid-promoted hydration reac-
tion using a combination of [PPh3AuCl] and AgOTf in
methanol-water afforded C6 ketone 7 with perfect regioselec-
tivity in excellent yield (94%) (Scheme 2).9,22
Chem. Lett. 2013, 42, 1374-1376
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1376
Seitz, L. Pohl, R. Pohlke, Angew. Chem., Int. Ed. Engl. 1969, 8, 447.
b) H. N. C. Wong, P. J. Garratt, F. Sondheimer, J. Am. Chem. Soc.
1974, 96, 5604. c) A. Krebs, J. Odenthal, H. Kimling, Tetrahedron
Lett. 1975, 16, 4663.
K. Tomooka, C. Iso, K. Uehara, M. Suzuki, R. Nishikawa-Shimono,
K. Igawa, Angew. Chem., Int. Ed. 2012, 51, 10355.
For general review on Mitsunobu reaction, see: O. Mitsunobu,
Synthesis 1981, 1. Recently, we have reported synthesis of nine-
membered heterocycles using intramolecular Mitsunobu reaction,
see: ref 5 and references cited therein.
a) S. Ohira, Synth. Commun. 1989, 19, 561. b) S. Müller, B. Liepold,
G. J. Roth, H. J. Bestmann, Synlett 1996, 521. c) G. J. Roth, B.
Liepold, S. G. Müller, H. J. Bestmann, Synthesis 2004, 59.
All new compounds were fully characterized by IR, 1H-, 13C NMR
and HRMS analysis: see, Supporting Information for details.
Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
The structures of 1b, (E)-2e, (Z)-2e, 7, 8, and 9 were determined by
X-ray crystallography. See the Supporting Information for details.
I
AcO
Ts
I
N
NIS, AcOH
Ts
N
+
1b
5
6
CH2Cl2, reflux
H
8 (42%)
9 (43%)
–OAc
N
7
8
I+
I
path a
N
Ts
a
Ts
b
8
9
10 The dynamic 1H NMR spectra were simulated using a gNMR
program: P. H. M. Budzelaar, gNMR (version 5.0.6.0), Ivory Soft,
2006.
11 Representative early work of di-iodination of alkyne with I2, see:
R. M. Noyes, R. G. Dickinson, V. Schomaker, J. Am. Chem. Soc.
1945, 67, 1319.
ii
iii
path b
I
I
12 It is known that halogenation reaction of strained cyclic alkyne, often
provides thermodynamically more favorable cis-product: a) G.
Wittig, H.-L. Dorsch, Justus Liebigs Ann. Chem. 1968, 711, 46. b)
R. Herges, A. Papafilippopoulos, K. Hess, C. Chiappe, D. Lenoir, H.
Detert, Angew. Chem., Int. Ed. 2005, 44, 1412.
Ts
N
9
N
Ts
X
X
iv
v
X = OAc or OH
13 Chloro-iodination of alkyne using n-Bu4NI in 1,2-dichloroethane,
see: M. L. Ho, A. B. Flynn, W. W. Ogilvie, J. Org. Chem. 2007, 72,
977.
Scheme 3. Ring contraction reactions of 1b.
14 The iodo-chlorination product contains a small amount of the
1
moiety, and its halogenation and protoiodination reactions
proceed with high trans-selectivity and regioselectivity to
afford well-functionalized 3-aza-5-[7]orthocyclophene deriva-
tives with stable planar chirality. Further studies on 3-aza-5-
[7]orthocyclophenes, including their stereochemical analysis
and asymmetric synthesis, are in progress.
regioisomer of (E)-2d (<5% molar content, as revealed by H NMR
analysis).
15 The regiochemistry of (E)-2d was determined by the correlation
between 13C of C5 position and methylene protons on at the C4
position in an HMBC experiment. See the Supporting Information for
details.
16 Protoiodination of alkyne with in situ generated HI, see: N. Kamiya,
Y. Chikami, Y. Ishii, Synlett 1990, 675.
17 A trace amount (<5%) of the regioisomer of (Z)-2e was observed in
This research was supported by MEXT, Japan [KAKENHI
(Nos. 22350019 and 24106734), Global COE Program (Kyushu
Univ.), and MEXT Project of Integrated Research on Chemical
Synthesis]. We thank Y. Tanaka (IMCE, Kyushu Univ.) for the
HRMS measurements.
1
crud products by H NMR analysis.
18 We found significant solvent effect on the stereochemistry of the
protoiodination reaction: a similar reaction performed in toluene
provided (E)-2e in 97%. See the Supporting Information for details.
19 Optimized geometries and natural population analysis of 1b and i
were computed by DFT calculation at B3LYP/6-311G(d,p) and
B3LYP/cep-121 g level of theory, respectively, by means of Gaussian
09 program (rev. C.01). See the Supporting Information for details.
20 For general review on electrophilic addition reaction of alkyne, see:
G. H. Schmid, in The Chemistry of The Carbon-Carbon Triple Bond,
ed. by S. Patai, Wiley, New York, 1978, Part 1, Chap. 8.
21 Experimental and theoretical investigations propose that electrophilic
di-halogenation of alkyne proceeds via halogen molecule-alkyne π
complex: a) R. Bianchini, C. Chiappe, G. L. Moro, D. Lenoir, P.
Lemmen, N. Goldberg, Chem.®Eur. J. 1999, 5, 1570. b) M. V.
Zabalov, S. S. Karlov, D. A. Lemenovskii, G. S. Zaitseva, J. Org.
Chem. 2005, 70, 9175; ref 12b.
This paper is dedicated to Professor Teruaki
Mukaiyama in celebration of the 40th anniversary of the
Mukaiyama aldol reaction.
References and Notes
1
For general reviews on cyclophanes, see: a) B. H. Smith, Bridged
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22 Hydration of alkyne using [PPh3AuCl] and AgOTf, see: Y. Fukuda,
K. Utimoto, J. Org. Chem. 1991, 56, 3729.
23 Orthocyclophene (Z)-2e shows fast interconversion between both the
enantiomers at RT. Details of the study on its stereochemical behavior
will be reported elsewhere.
24 Small peaks (tR = 13.6 and 17.5 min) of HPLC chart (c) and (d) are
probably the regioisomer of (E)-2d, see: ref 14.
2
Y. Tobe, M. Sonoda, in Modern Cyclophane Chemistry, ed. by
R. Gleiter, H. Hopf, Wiley-VCH, Weinheim, 2004, Chap. 1.
doi:10.1002/3527603964.ch1.
25 Enol ester synthesis from alkyne using AcOH and NXS, see: N.
Okamoto, Y. Miwa, H. Minami, K. Takeda, R. Yanada, J. Org. Chem.
2011, 76, 9133.
3
4
A. C. Cope, M. W. Fordice, J. Am. Chem. Soc. 1967, 89, 6187.
Representative study on medium-sized orthocyclophynes, see: a) G.
26 The related intramolecular Friedel-Crafts reaction of an epoxide
derivative of 2 has been reported. See ref 5.
Chem. Lett. 2013, 42, 1374-1376
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/