Synthesis of orthogonally protected angular nitrogen polyheterocycles via CpCo-catalyzed pyridine formation

Article abstract of DOI:10.1055/s-0030-1258041

Unprecedented nitrogen polyheterocycles have been prepared by means of intramolecular Co-catalyzed [2+2+2] cycloaddition of two alkynes to one nitrile. They exhibit two nitrogen-containing rings fused in an angular fashion to one pyridine unit. Several relative positions of the nitrogen atoms have been studied, giving rise to eight different new scaffolds. In order to allow selective functionalization of the two amino groups, orthogonal protecting groups (PG¹ and PG²) were introduced prior to cyclization. Eleven combinations of seven different protecting groups (Bn, COCF₃, Cbz, Boc, Ts, SO₂-2-py, Ns) were tested, most of them being perfectly tolerated under the cyclization conditions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258041

2314
LETTER
Synthesis of Orthogonally Protected Angular Nitrogen Polyheterocycles via
CpCo-Catalyzed Pyridine Formation
C
pCo-Catalyze
d
P
v
yridine For
m
e
ation s Miclo,a Pierre Garcia,a Yannick Evanno,b Pascal George,b Mireille Sevrin,b Max Malacria,*a
Vincent Gandon,*a Corinne Aubert*a
a
UPMC Univ Paris 06, IPCM UMR 7201, FR2769, 4 Place Jussieu, 75252 Paris Cedex 05, France
Fax +33(1)44277360; E-mail: vincent.gandon@u-psud.fr; corinne.aubert@upmc.fr,
Sanofi-Aventis R&D, CNS Research Department, 31 Avenue Paul Vaillant-Couturier, 92220 Bagneux, France
b
Received 1 July 2010
Type E products were assembled by means of intramolec-
Abstract: Unprecedented nitrogen polyheterocycles have been pre-
pared by means of intramolecular Co-catalyzed [2+2+2] cycloaddi-
tion of two alkynes to one nitrile. They exhibit two nitrogen-
containing rings fused in an angular fashion to one pyridine unit.
Several relative positions of the nitrogen atoms have been studied,
giving rise to eight different new scaffolds. In order to allow selec-
tive functionalization of the two amino groups, orthogonal protect-
ing groups (PG1 and PG2) were introduced prior to cyclization.
Eleven combinations of seven different protecting groups (Bn,
COCF3, Cbz, Boc, Ts, SO2-2-py, Ns) were tested, most of them be-
ing perfectly tolerated under the cyclization conditions.
ular rhodium-catalyzed [2+2+2] cycloadditions of two
alkynes to one nitrile.6
PG1
PG1
PG1
N
N
N
N
N
N
N
N
N
PG2
PG2
PG2
SiMe3
SiMe3
SiMe3
Key words: alkyne, cobalt, cycloaddition, nitrile, pyridine
A
B
C
PG1
PG1
PG1
N
N
N
N
The development of synthetic methods aimed at the rapid
construction of nitrogen heterocycles is of prime impor-
tance to sustain pharmaceutical innovation. Moreover, it
is highly desirable that such methods grant an easy access
to products that can be selectively functionalized at vari-
ous sites to allow to set up large libraries of potential
leads. Due to its compatibility with many protecting
groups, the transition-metal-mediated [2+2+2]-cycloaddi-
tion reaction should address these two issues.1 Pertaining
to this idea is the recent work of Snyder who reported a
[2+2+2]-cycloaddition approach to tricyclic pyridines
fused to one nitrogen and one oxygen heterocycle.2 The
resulting 5,6,7,8-tetrahydro-1,6-naphthyridine scaffold
could be used to build up a rich library of compounds after
deprotection and functionalization of the nitrogen atom of
the piperidine moiety.3
PG2
N
PG2
N
PG2
N
N
N
D
E
F
PG1
N
PG1
N
PG2
N
N
N
N
PG2
G
H
PG1
N
N
N
PG2
I
We have recently reported the first [2+2+2] cycloaddi-
tions involving an ynamide,4 a nitrile, and an alkyne to
give scaffolds of type A–C displaying two functionaliz-
able nitrogen heterocycles (Figure 1).5 We reasoned that
the introduction of orthogonal protecting groups would
dramatically increase the possibility of peptide couplings
or other typical transformations used in combinatorial
chemistry. We now report on our efforts to synthesize or-
thogonally protected polyheterocycles displaying one of
the eight scaffolds D–K. To the best of our knowledge,
PG1
PG1
N
N
PG2
N
N
N
N
PG2
K
J
Figure 1
these frameworks are all unprecedented to date, except E This paper prompted us to report our own results in that
which was just reported by Pla–Quintana and Roglans.6a field. Our approach to these pyridines, twice fused to pyr-
rolidine, piperidine, or azepane rings in an angular fash-
ion, relies on the cobalt-catalyzed [2+2+2] cycloaddition
of diyne nitriles according to Scheme 1.
SYNLETT 2010, No. 15, pp 2314–2318
Advanced online publication: 12.08.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0030-1258041; Art ID: G19210ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
CpCo-Catalyzed Pyridine Formation
2315
PG1
PG1
nitrile from byproducts and unreacted compound 15. Re-
moval of the COCF3 group16 allowed partial purification,
and finally, reinstatement of the protecting group and
flash chromatography furnished 1f in analytically pure
form.
N
N
CpCo(CO)2 (5 mol%)
PG2
N
PG2
N
toluene, reflux, hν
N
N
1a–s
2a–s
HO
OTBDMS
Scheme 1 Cobalt-catalyzed [2+2+2] cycloaddition of orthogonally
protected diyne nitriles
b
Cbz
N
11
Cbz
N
O
NH2
+
H
MsO
OTBDMS
12
a
NCbz
The following protecting groups were incorporated in the
substrates: benzyl (Bn), trifluoroacyl (COCF3), benzylox-
ycarbonyl (Cbz), tert-butoxycarbonyl (Boc), p-toluene-
sulfonyl (Ts), 2-pyridylsulfonyl (SO2-2-py), and 2-
nitrobenzene-sulfonyl (Ns).7,8 Representative examples of
diyne nitriles synthesis exhibiting orthogonal combina-
tions of protecting groups are shown in Schemes 2– 5. For
instance, compound 1d, potential precursor of a type D
scaffold with COCF3 (PG2) and Cbz (PG1) protecting
groups, was obtained in six steps starting from propargyl
amine, first protected as trifluoroamide 3 using ethyl trif-
luoroacetate (Scheme 2).9 Butyne 1,4-diol monotetrahy-
dropyranyl ether 410 was converted into the corresponding
mesylate 5. The reaction of 3 with 5 under basic condi-
tions led to diyne 6 in 90% yield. This compound was
deprotected to give alcohol 7, subsequently transformed
into bromide 8. Lastly, the bromide was coupled with car-
bamate 9,11 previously deprotonated using sodium hy-
dride.
c
10
O
NHCOCF3
X
d
15
N
X = OTBDMS (13)
X = OH (14)
CbzN
NX
e, f
X = H (16)
X = COCF3 (1f)
g
N
Scheme 3 Synthesis of diyne nitrile 1f. Reagents and conditions: a)
CH2Cl2, 0 °C to r.t., overnight, 84%; b) MsCl, Et3N, CH2Cl2, 0 °C, 1
h, 93%; c) NaH (1 equiv), DMF, 0 °C to r.t., overnight, 74%; d) TBAF
(1.5 equiv), THF, r.t., 12 h, 68%; e) Bu3P (1.1 equiv), ADDP (1.0
equiv), 15 (2.0 equiv), toluene, 0 °C; f) K2CO3, 95% EtOH, r.t., over-
night; g) (F3CCO)2O (1.2 equiv), Et3N, CH2Cl2, r.t., 30 min, 70%
yield (3 steps).
Potential precursors to scaffold F were prepared in a sim-
ilar fashion from carbamate 10 and alcohol 17
(Scheme 4).10 The latter was reacted under Mitsunobu re-
action conditions with TsNHBoc17 to yield 18 which was
deprotected into 19 and then brominated to give 20. Cou-
HO
OTHP
b
COCF3
4
COCF3
N
N
H
NH2
+ F3CCO2Et
THPO
X
OH
a
MsO
OTHP
a
5
17
Boc
3
c
N
Ts
Cbz
N
H
X = OTHP (18)
X = OH (19)
X = Br (20)
X
Cbz
N
b
c
Cbz
N
X = OTHP (6)
X = OH (7)
X = Br (8)
H
d
e
N
F3COCN
NCbz
N
9
d
f
10
1d
XBocN
NX
Scheme 2 Synthesis of diyne nitrile 1d. Reagents and conditions: a)
F3CCO2Et, MeOH, 0 °C to r.t., overnight, 92%; b) MsCl, Et3N,
CH2Cl2, 0 °C to r.t., 2 h, 100%; c) NaH (1 equiv), TBAI (10 mol%),
THF, 0 °C to reflux, 2 h, 90%; d) PTSA·H2O (1 mol%), MeOH, r.t.,
1 h, 71%; e) CBr4, Ph3P, CH2Cl2, 0 °C to r.t., 2 h, 100%; f) NaH,
DMF, –60 °C to r.t., 2 h, 63%.
N
X = Ts (21)
X = H (22)
e
CbzN
f
N
X = Boc (1i)
X = H (23)
X = COCF3 (1j)
or X = Bn (1k)
g
h
i
The synthesis of 1f (Scheme 3), potential precursor of a
type E scaffold with PG1 = COCF3 and PG2 = Cbz, was
implemented the other way round, that is, by Cbz protec-
tion of propargyl amine first.12 The resulting carbamate 10
was then coupled under basic conditions to mesylate 12,
previously prepared from alcohol 11.13 Diyne 13 was then
desilylated into alcohol 14, which was subject to Mitsuno-
bu reaction conditions14 with nitrile-amide 15, prepared
the same way as 3 (same conditions, same yield).15 Unfor-
tunately, it was not possible to separate the resulting diyne
Scheme 4 Synthesis of diyne nitriles 1i–k. Reagents and conditi-
ons: a) Ph3P (1.0 equiv), DIAD (1.0 equiv), TsNHBoc (1.0 equiv),
THF, r.t., 2 h, 73%; b) PTSA·H2O (5 mol%), MeOH, r.t., 1 h, 80%; c)
CBr4, Ph3P, THF, r.t., 3 h, 90%; d) KHMDS (1 equiv), TBAI (10
mol%), THF, r.t. to reflux, 1 h, 70%; e) Mg (5 equiv), MeOH, sonica-
tion, r.t., 30 min, 86%; f) KOt-Bu (0.3 equiv), t-BuOH–DMF (1:1),
0 °C, 10 min, then acrylonitrile (2 equiv), 0 °C, 1 h, 78%; g) TFA,
CH2Cl2, r.t., 15 min, 73%; h) (F3CCO)2O (1.2 equiv), Et3N (1.5
equiv), CH2Cl2, 0 °C, 2 min, 78%; i) BnBr (8 equiv), Et3N, reflux, 4
h, 42%.
Synlett 2010, No. 15, 2314–2318 © Thieme Stuttgart · New York

2316
Y. Miclo et al.
LETTER
pling of 10 and 20 was then followed by gentle tosyl These compounds, as all those exhibiting a Cbz group at
deprotection using Mg/MeOH under sonication.18 The re- PG2, exist as slow interconverting rotamers in CDCl3 at
sulting diyne was deprotonated by KOt-Bu prior to conju- room temperature, making their characterization quite dif-
gate addition onto acrylonitrile to generate 1i. The Boc ficult. At higher temperature, the peaks sharpen to give
group was removed using trifluoroacetic acid and re- the expected number of signals. For instance, the coales-
placed either by COCF3 (1j) or Bn (1k).
cence of the pyridine proton of 2f, which appears as two
singlets around d = 8 ppm at 22 °C, is observed at 30 °C,
whereas the benzyl protons coalesce at 50 °C (Figure 2).
In the F series, we were able to prepare three 5/6/7-tricy-
clic pyridines in 71% (2i), 89% (2j), and 78% (2k) yield.
Three members of the F series could be obtained in good
to high yields. The G series showed the compatibility of
the 2-pyridylsulfonyl group, 2l being obtained in 68%
yield. On the other hand, in the presence of a Ns group,
2m was obtained in 19% yield only, accompanied by deg-
radation byproducts. Compound 2o, corresponding to
scaffold H, was obtained in 76% yield. For scaffold I, the
2-pyridylsulfonyl group was well tolerated at PG1, the tri-
cyclic pyridine being isolated in 74% yield. Lastly, repre-
sentatives of the J and K families could be isolated, yet in
decreasing yields.
Our synthetic approach to the larger diyne nitriles 1l–n,
potential precursors of scaffold G, is depicted in
Scheme 5. Alcohol 2419 and TsNHBoc were reacted un-
der standard Mitsunobu conditions to give 25, from which
the tosyl group was subsequently removed and replaced
by a propargyl moiety. The tetrahydropyranyl residue was
displaced under acidic conditions, and the resulting alco-
hol was submitted to a second Mitsunobu reaction with
aminonitriles bearing SO2-2-pyridyl (29)20 or nosyl (30)21
protecting group at the nitrogen atom, yielding diyne ni-
triles 1l and 1m, respectively. The latter was used to syn-
thesize 1n after straightforward deprotection of the nosyl
group using thiophenol and potassium carbonate8b fol-
lowed by introduction of the benzyloxycarbonyl group as
for 10.
Table 1 Results of the Cyclizations of Compounds 1a–s
Boc
X
OH
N
BocN
BocN
Scaffold PG1
PG2
Ts
Product
2a
2b
2c
Yield (%)a
55b
71b
91b
76c
85
Br
A
B
C
D
D
E
E
E
F
Cbz
a
e
c
YHN
Cbz
Ts
N
Cbz
Ts
N
Y = SO2-2-py (29)
Y = Ns (30)
OTHP
OTHP
X
N
X
Cbz
COCF3
Bn
2d
2e
24
Y = SO2-2-py (1l)
Y = Ns (1m)
Y = H (31)
Cbz
X = Ts (25)
X = H (26)
X = OTHP (27)
X = OH (28)
b
d
f
g
COCF3
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Boc
Boc
Boc
Cbz
Boc
Ts
2f
96
Y = Cbz (1n)
2g
2h
2i
90
Scheme 5 Synthesis of diyne nitriles 1l–n. Reagents and conditions:
a) Ph3P (1.0 equiv), DIAD (1.0 equiv), TsNHBoc (1.0 equiv), THF,
r.t., 1 h, 84%; b) Mg (5 equiv), MeOH, sonication, r.t., 30 min, 76%;
c) KHMDS (1 equiv), THF, 0 °C, 10 min, then propargyl bromide,
r.t., 2 h, 66%; d) PTSA·H2O (5 mol%), MeOH, r.t., 1 h, 94%; e) Ph3P
(1.0 equiv), DIAD (1.0 equiv), 29 (1.0 equiv), THF, r.t., 1 h, 55%; or
Ph3P (1.5 equiv), DIAD (1.0 equiv), 30 (1.0 equiv), THF, r.t., 1 h,
48%; f) PhSH (1.3 equiv), K2CO3 (2 equiv), DMF, r.t., 30 min, 74%;
g) N-(benzyloxycarbonyloxy)succinimide (1.3 equiv), CH2Cl2, r.t.,
overnight, 84%.
Bn
91
Boc
71
F
COCF3
Bn
2j
89
F
2k
2l
78
G
G
G
H
I
SO2-2-py
Ns
68
2m
2n
2o
2p
2q
2r
19
With the diyne nitriles in hand, we carried out cobalt-
catalyzed [2+2+2] cycloadditions using 5 mol% of
CpCo(CO)2 under refluxing conditions and visible-light
irradiation,22 as shown in Scheme 1. Gratifyingly, these
experimental conditions gave birth to scaffolds D–J in
good yields (Table 1).23 Any orthogonal combination of
Cbz, Ts, COCF3, Boc, and Bn groups were tolerated dur-
ing the cyclization processes. For instance, in the D series,
products 2d and 2e, displaying Cbz/COCF3 and Cbz/Bn
combinations at PG1 and PG2, were isolated in 76% and
85%, respectively. It is worthy of note that the synthesis
of 2d could be scaled up to 3 grams. The best results were
observed in the E series, the naphthyridines 2f, 2g, and 2h
being isolated in 96%, 90%, and 91% yield, respectively.
Cbz
83
Boc
76
SO2-2-py
Cbz
74
J
56
K
K
Boc
Cbz
Ns
30
Boc
2s
15
a Isolated yields, 0.2–0.8 mmol scale unless stated otherwise.
b See ref. 5.
c 7.65 mmol scale (3 g).
Synlett 2010, No. 15, 2314–2318 © Thieme Stuttgart · New York

LETTER
CpCo-Catalyzed Pyridine Formation
2317
A closer look at Table 1 suggests that low to moderate
yields (<60%) may not only be attributed to the protecting
groups (like in 2m) but also to the size of the left ring
(2a,q,r,s). Obviously the formation of 4- and 7- is more
difficult than that of 5- and 6-membered cycles. This
could be due to a slower coupling of the two alkyne units
on the way to the key cobaltacyclopentadiene intermedi-
ate [Scheme 6, pathway (i)].24
R2
N
R2
N
R2N
N
(i)
N
R1N
R1N
Co
Cp
CoCp
N
CoCp
N
R1
R2
N
R2
N
R2
N
(ii)
N
N
R1N
Co
Cp
Co
R1N
R1N
N
Cp
CoCp
Scheme 6 Mechanistic options for the synthesis of pyridines as pro-
posed in ref. 25
This step, which precedes the insertion of the nitrile to
give a cobalt(V) carbene and then its rearrangement into
the pyridine nucleus, is supposed to be thermodynamical-
ly more favorable than the alkyne–nitrile coupling fol-
lowed by alkyne cycloaddition [pathway (ii)].25 Thus, if
pathway (i) is the only viable option for the assembly of
pyridines, the decrease of its rate may bring up competi-
tive reactions such as intermolecular oligomerizations.26
Figure 2 1H NMR spectra of 2f (CDCl3) at various temperatures
In conclusion, we have been able to prepare new hetero-
cyclic scaffolds by means of cobalt-catalyzed [2+2+2] cy-
cloaddition of diyne nitriles. They are composed of a
pyridine unit fused to two heterocycles of the pyrrolidine,
piperidine, or azepane family. Our goal was not only to
open an expedient route to these new polycyclic com-
pounds, but also to facilitate potential functionalization by
the orthogonal protection strategy. This was made possi-
ble by the extensive level of chemoselectivity of the
[2+2+2]-cycloaddition process. Among the seven differ-
ent protecting groups used, six proved perfectly compati-
ble with the cyclization process. We now wish to create
libraries from these compounds and evaluate their biolog-
ical properties.
23, 539. (b) Varela, J.; Saá, C. Chem. Rev. 2003, 103, 3787.
(c) Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503.
(d) Gandon, V.; Aubert, C.; Malacria, M. Curr. Org. Chem.
2005, 9, 1699. (e) Kotha, S.; Brahmachary, E.; Lahiri, K.
Eur. J. Org. Chem. 2005, 4741. (f) Gandon, V.; Aubert, C.;
Malacria, M. Chem. Commun. 2006, 2209. (g) Chopade,
P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307.
(h) Agenet, N.; Gandon, V.; Buisine, O.; Slowinski, F.;
Aubert, C.; Malacria, M. In Organic Reactions, Vol. 68;
RajanBabu, T. V., Ed.; John Wiley and Sons: Hoboken,
2007, 1–302. (i) Heller, B.; Hapke, M. Chem. Soc. Rev.
2007, 36, 1085. (j) Tanaka, K. Synlett 2007, 1977.
(k) Maryanoff, B. E.; Zhang, H.-C. ARKIVOC 2007, (xii), 7.
(l) Varela, J.; Saá, C. Synlett 2008, 2571. (m) Tanaka, K.
Chem. Asian J. 2009, 4, 508. (n) Hess, W.; Treutwein, J.;
Hilt, G. Synthesis 2008, 3537. (o) Shibata, T.; Tsuchikama,
K. Org. Biomol. Chem. 2008, 1317.
Acknowledgment
(p) Scheuermann née Taylor, C. J.; Ward, B. D. New J.
Chem. 2008, 32, 1850. (q) Lebuf, D.; Gandon, V.; Malacria,
M. In Handbook of Cyclization Reactions, Vol. 1; Ma, S.,
Ed.; Wiley-VCH: Weinheim, 2009, 367–406.
We thank the IUF, Ministère de la Recherche, and CNRS for finan-
cial support of this work. P.G. and Y.M. are thankful to Sanofi-
Aventis and Sanofi-Synthelabo, respectively, for PhD grants.
(2) Zhou, Y.; Porco, J. A.; Snyder, J. K. Org. Lett. 2007, 9, 393.
(3) Zhou, Y.; Beeler, A. B.; Cho, S.; Wang, Y.; Franzblau, S. G.;
Snyder, J. K. J. Comb. Chem. 2008, 10, 534.
(4) For recent reviews on the chemistry of ynamides, see:
(a) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem. Int. Ed.
2010, 49, 2840. (b) DeKorver, K. A.; Li, H.; Lohse, A. G.;
Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2010, in press; DOI: 10.1021/cr100003s.
References and Notes
(1) For reviews on [2+2+2] cycloaddition reactions, see:
(a) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984,
Synlett 2010, No. 15, 2314–2318 © Thieme Stuttgart · New York

2318
Y. Miclo et al.
LETTER
(5) Garcia, P.; Moulin, S.; Miclo, Y.; Leboeuf, D.; Gandon, V.;
Aubert, C.; Malacria, M. Chem. Eur. J. 2009, 15, 2129.
(6) Examples of intramolecular [2+2+2] cycloaddition of two
alkynes to one nitrile are rare, see ref. 2, 3, 5, and:
(a) Garcia, L.; Pla-Quintana, A.; Roglans, A.; Parella, T.
Eur. J. Org. Chem. 2010, 3407. (b) Meißner, A.; Groth, U.
Synlett 2010, 1051. (c) Chang, H.-T.; Jeganmohan, M.;
Cheng, C.-H. Org. Lett. 2007, 9, 505. (d) Yamomoto, Y.;
Kinpara, K.; Ogawa, R.; Nishiyama, H.; Itoh, K. Chem. Eur.
J. 2006, 12, 5618. (e) Groth, U.; Huhn, T.; Kesenheimer, C.;
Kalogerakis, A. Synlett 2005, 1758. (f) Nicolaus, N.;
Strauss, S.; Neudörfl, J.-M.; Prokop, A.; Schmalz, H.-G.
Org. Lett. 2009, 11, 341.
(7) (a) Green, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons: New
York, 1999. (b) Kocieński, P. J. Protecting Groups, 3rd ed.;
Thieme: Stuttgart, 2005.
(8) The 2-pyridylsulfonyl group can be easily cleaved using for
instance magnesium in methanol, see: (a) Pak, C. S.; Lim,
D. S. Synth. Commun. 2001, 31, 2209. (b) On the other
hand, the 2-nitrobenzenesulfonyl group can be removed
using for instance thiophenol in the presence of potassium
carbonate, see: Fukuyama, T.; Jow, C.-K.; Cheung, M.
Tetrahedron Lett. 1995, 36, 6373.
irradiated (visible light) using a 300 W halogen lamp until
completion of the reaction (TLC monitoring). After removal
of the volatiles under reduced pressure, the crude mixture
was purified by flash chromatography (gradient mixtures of
PE and EtOAc), affording the corresponding tricyclic
pyridines.
Compound 2f: 1H NMR (400 MHz, C6D6, 70 °C): d = 2.84
(t, J = 6.0 Hz, 2 H), 3.46 (br s, 2 H), 4.18 (s, 2 H), 4.24 (br
s,2 H), 4.44 (br s, 2 H), 5.30 (s, 2 H), 7.20–7.31 (m, 3 H),
7.45 (d, J = 7.6 Hz, 2 H), 8.14 (s, 1 H). 13C NMR (100 MHz,
C6D6): d = 31.0–32.2 (CH2), 41.2–42.1 (CH2), 42.8–43.4
(CH2), 49.5–49.9 (CH2), 50.4–50.7 (CH2), 67.3 (CH2),
117.03 (q, J = 286 Hz, CF3), 121.7–121.9 (C), 128.4 (CH),
128.5 (CH), 128.8 (CH), 131.3-131.7 (C), 137.4 (C), 142.3–
142.9 (m, CH), 143.1–143.4 (C), 151.5–151.6 (C), 155.5 (q,
J = 36 Hz, C). 19F NMR (376 MHz, CDCl3): d = –69.7. IR
(neat): 3089, 3064, 3033, 2949, 2864, 1689, 1138, 730 cm–1.
Mp 144.1 °C. HRMS: m/z calcd for C20H19O3N3F3:
406.1370; found: 406.13727.
Compound 2i: 1H NMR (400 MHz, CDCl3): d = 1.46 (s, 9
H), 2.78 (br s, 2 H), 3.17 (br s, 2 H), 3.59 (br s, 4 H), 4.69–
4.72 (2 s, 2 H), 4.78 (br s, 2 H), 5.20 (s, 2 H), 7.28–7.41 (m,
5 H), 8.22–8.28 (2 s, 1 H). 13C NMR (100 MHz, CDCl3):
d = 28.5 (CH3), 28.7 (CH2), 31.3–31.8 (m, CH2), 40.1–45.9
(m, 2 CH2), 50.7–51.2 (CH2), 51.3–51.8 (CH2), 67.3–67.4
(CH2), 80.1 (C), 128.0 (CH), 128.3 (CH), 128.6 (CH),
130.5–131.4 (m, 2 C), 136.6 (C), 140.8–140.9 (CH), 145.6–
145.9 (m, 2 C), 154.7–155.0 (C), 159.7 (C). IR (neat): 2974,
1692, 1414 cm–1. Mp 154.1 °C. HRMS: m/z calcd for
C24H30O4N3: 424.22308; found: 424.22297.
(9) Cruickshank, K. A.; Stockwell, D. L. Tetrahedron Lett.
1988, 29, 5221.
(10) Brillon, D.; Deslongchamps, P. Can. J. Chem. 1987, 65, 43.
(11) Summa, V.; Petrocchi, A.; Matassa, V. G.; Gardelli, C.;
Muraglia, E.; Rowley, M.; Paz Gonzalez, O.; Laufer, R.;
Monteagudo, E.; Pace, P. J. Med. Chem. 2006, 49, 6646.
(12) Masquelin, T.; Obrecht, D. Synthesis 1995, 276.
(13) (a) McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D.
J. Org. Chem. 1986, 51, 3388. (b) Guorong, C.; Wei, Z.;
Dawei, M. Tetrahedron 2006, 62, 5697.
Compound 2k: 1H NMR (400 MHz, CDCl3): d = 2.52–2.59
(m, 4 H), 2.68–2.73 (m, 2 H), 3.08–3.10 (m, 2 H), 3.55 (s, 2
H), 4.56 (s, 1 H), 4.61 (s, 1 H), 4.67 (s, 1 H), 4.69 (s, 1 H),
5.12 (s, 2 H), 7.15–7.30 (m, 11 H), 8.10–8.15 (2 s, 1 H). 13
C
(14) Hughes, D. L. In Organic Reactions, Vol. 42; John Wiley
NMR (100 MHz, CDCl3): d = 30.7–30.8 (CH2), 39.3 (CH2),
50.7–51.1–51.2–51.6 (mixture of slow interconverting rota-
mers) (2 CH2), 53.7 (CH2), 54.2 (CH2), 63.5 (CH2), 67.3
(CH2), 127.2 (CH), 128.0 (CH), 128.2 (CH), 128.4 (CH),
128.6 (CH), 129.1 (CH), 130.1–131.1 (C), 131.4–131.6 (C),
136.7 (C), 138.5 (C), 140.5–140.8 (CH), 144.5–144.8 (C),
154.8 (C), 161.1–161.2 (C).IR (neat): 2942, 1703, 1412 cm–1.
HRMS: m/z calcd for C23H28O2N3: 414.21760; found
414.21754.
and Sons: Hoboken, 1992.
(15) The use of standard Mitsunobu conditions, Ph3P/DEAD,
proved less efficient than Bu3P/ADDP: Tsunoda, T.;
Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639.
(16) Bergeson, R. J.; McManis, J. S. J. Org. Chem. 1988, 53,
3108.
(17) Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379.
(18) Nyasse, B.; Grehn, L.; Regnarsson, U. Chem. Commun.
1997, 1017.
(23) It is worthy of note that attempts to cyclize monoprotected
diyne nitriles such as 16, 23, or 31 failed.
(19) Efskind, J.; Römming, C.; Undheim, K. J. Chem. Soc.,
Perkin Trans. 1 2001, 2697.
(24) For theoretical calculations on the formation of cobalta-
cyclopentadienes and their reactivity, see: (a) Xu, R.;
Winget, P.; Clark, T. Eur. J. Inorg. Chem. 2008, 2874.
(b) Agenet, N.; Gandon, V.; Vollhardt, K. P. C.; Malacria,
M.; Aubert, M. C. J. Am. Chem. Soc. 2007, 129, 8860.
(c) Aubert, C.; Gandon, V.; Geny, A.; Heckrodt, T. J.;
Malacria, M.; Paredes, E.; Vollhardt, K. P. C. Chem. Eur. J.
2007, 13, 7466. (d) Gandon, V.; Agenet, N.; Vollhardt, K. P.
C.; Malacria, M.; Aubert, C. J. Am. Chem. Soc. 2006, 128,
8509. (e) Dahy, A. A.; Koga, N. Bull. Chem. Soc. Jpn. 2005,
78, 781. (f) Dahy, A. A.; Suresh, C. H.; Koga, N. Bull.
Chem. Soc. Jpn. 2005, 78, 792. (g) Veiros, L. F.; Dazinger,
G.; Kirchner, K.; Calhorda, M. J.; Schmid, R. Chem. Eur. J.
2004, 10, 5860.
(20) Marquis, R. W.; Ru, Y.; LoCastro, S. M.; Zeng, J.;
Yamashita, D. S.; Oh, H.-J.; Erhard, K. F.; Davis, L. D.;
Tomaszek, T. A.; Tew, D.; Salyers, K.; Proksch, J.; Ward,
K.; Smith, B.; Levy, M.; Cummings, M. D.; Haltiwanger,
R. C.; Trescher, G.; Wang, B.; Hemling, M. E.; Quinn, C. J.;
Cheng, H.-Y.; Lin, F.; Smith, W. W.; Janson, C. A.; Zhao,
B.; McQueney, M. S.; D’Alessio, K.; Lee, C.-P.; Marzulli,
A.; Dodds, R. A.; Blake, S.; James, I. E.; Gress, C. J.;
Bradley, B. R.; Lark, M. W.; Gowen, M.; Veber, D. F.
J. Med. Chem. 2001, 44, 1380.
(21) Excellent yields of Mitsunobu reactions in the presence of
the 2-nitrobenzenesulfonyl group have been reported, see
ref. 8b.
(22) (a) For technical details about the visible light irradiation,
see: Agenet, N.; Mirebeau, J.-H.; Petit, M.; Thouvenot, R.;
Gandon, V.; Malacria, M.; Aubert, C. Organometallics
2007, 26, 819. (b) Procedure for [2+2+2] Cycloadditions
To a refluxing solution of the starting material in xylenes (c
0.1 M) under argon was added 5 mol% of
(25) For a DFT study of the mechanism of pyridine formation via
[2+2+2] cycloaddition, see: Dazinger, G.; Torres-Rodrigues,
M.; Kirchner, K.; Calhorda, M. J.; Costa, P. J. J. Organomet.
Chem. 2006, 691, 4434.
(26) Also we cannot exclude catalyst deactivation by the Ns
group.
cyclopentadienyledicarbonyl cobalt, and the mixture was
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