Synthesis of tricyclic fused 3-aminopyridines through intramolecular Coi-catalyzed [2+2+2] cycloaddition between ynamides, nitriles, and alkynes

Article abstract of DOI:10.1002/chem.200802301

The first [2+2+2] cocyclizations between ynamides, nitriles, and alkynes are reported. They open a new access to unprecedented nitrogen-containing heterocycles of type 2-trimethylsilyl-3-aminopyridines. Such frameworks, which can be found in various compo

Full text of DOI:10.1002/chem.200802301

FULL PAPER
DOI: 10.1002/chem.200802301
Synthesis of Tricyclic Fused 3-Aminopyridines through Intramolecular CoI-
Catalyzed [2+2+2] Cycloaddition between Ynamides, Nitriles, and Alkynes
Pierre Garcia, Solenne Moulin, Yves Miclo, David Leboeuf, Vincent Gandon,
Corinne Aubert,* and Max Malacria*[a]
Abstract: The first [2+2+2] cocycliza-
tions between ynamides, nitriles, and
alkynes are reported. They open a new
access to unprecedented nitrogen-con-
taining heterocycles of type 2-trime-
thylsilyl-3-aminopyridines. Such frame-
works, which can be found in various
compounds of biological interest, are
very difficult to prepare by convention-
al methods. However, using [CpCo-
AHCTNUTGERG(NNUN C2H4)2] (Cp=cyclopentadienyl) as cat-
alyst, the intramolecular cyclizations
could be achieved in up to 100% yield.
The presence of the trimethylsilyl
group allowed a rare type of Hiyama
cross-coupling: one of the silylated pyr-
idines could be coupled with p-iodoani-
sole to give a new type of biaryl
system.
Keywords: alkynes · cobalt · cyclo-
addition · Hiyama cross-coupling ·
pyridine
Introduction
Pyridines are ubiquitous subunits of natural products and
pharmaceuticals.[1] Thus, the construction of complex poly-
cyclic pyridines remains an important synthetic goal for cre-
ating new and potentially useful systems with biological ap-
plications. Among the possible methods to achieve this, the
transition-metal-catalyzed [2+2+2] cycloaddition reaction
between two alkynes and one nitrile is probably one of the
Scheme 1. Prototypical [2+2+2] cycloaddition leading to heterosubsti-
tuted pyridines.
C2 and/or C3 can be found, and they are strictly restricted
to silicon (X=Si or X=Y=Si).[6]
ꢀ
most elegant, as it allows the formation of the two C C and
ꢀ
the C N bonds of the pyridine ring in a single operational
We reasoned that 2-trimethylsilyl-3-aminopyridines (X=
N, Y =Si) could be possibly assembled by carrying out un-
precedented [2+2+2] cocyclizations between an ynamide,
an alkyne, and a nitrile (Scheme 2).[7] In an intramolecular
fashion, this strategy would provide an entry into new poly-
cyclic systems displaying frameworks that can be found in
various compounds of biological interest.[1] We report herein
our efforts to prepare polyunsaturated precursors of type 1
and their subsequent cobalt-catalyzed cyclizations[8] to give
tricyclic fused 2-trimethylsilyl-3-aminopyridines 2. We also
show how we could take advantage of the presence of the
step.[2,3] In principle, this atom-and-step economy procedure,
which is tolerant to a wide range of functional groups,
should enable the direct formation of polycyclic functional-
ized pyridines, or at least inherently functionalizable ones
owing to the presence of heteroatoms. The incorporation of
an heteroatom at C2 has been achieved frequently by [2+
2+2] cycloaddition reactions with silicon (Scheme 1, Y=
Si),[4] and rarely with phosphorus (Y=P).[5] On the other
hand, very few examples of pyridines heterosubstituted at
[a] P. Garcia, S. Moulin, Dr. Y. Miclo, D. Leboeuf, Dr. V. Gandon,
Dr. C. Aubert, Prof. Dr. M. Malacria
Laboratoire de Chimie Organique UMR 7611
Institut de Chimie Molꢀculaire FR2769
Universitꢀ Pierre et Marie Curie Paris 6
Tour 44–54, 4 place Jussieu 75252 Paris (France)
Fax : (+33)144-27-73-60
E-mail: corinne.aubert@upmc.fr
Scheme 2. Synthetic strategy for the formation of tricyclic fused 2-trime-
thylsilyl-3-aminopyridines and subsequent cross-coupling.
max.malacria@upmc.fr
Chem. Eur. J. 2009, 15, 2129 – 2139
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2129

trimethylsilyl group to achieve an easier-than-expected
Hiyama cross-coupling.
TsNHBoc (Boc=tert-butyl oxycarbonyl) (h).[10] Lastly, the
Boc group was removed (i)[11] and alkynylation was achieved
using Witulskiꢂs procedure[12] with the iodonium salt 7 (j).[13]
Overall, these steps proceeded with good to excellent yields,
except for the formation of the ynamides (31–45%), which
is always a delicate matter requiring specific precautions.
Compounds 1d–h, which exhibit only one nitrogen tether,
could also be constructed relatively rapidly from ynols in a
similar fashion (Schemes 4 and 5). The starting material was
first protected at the oxygen (Scheme 4, a or c, Z=THP,
ethoxyethyl (EE), or Ts) and the alkyne was alkylated using
the iodide 8 (b), or ethylene oxide (d), to give 9d–f. These
alcohols were submitted to Mitsunobu reaction conditions
using TsNHBoc (e). The protecting group Z was removed
(f), and the resulting alcohols were mesylated (g). Cyanation
with NaCN or KCN was performed next (h). Of particular
note is the efficient deprotection of the Boc group of inter-
mediates 10d–f upon treatment with NaCN in DMF to form
11d–f in very good overall yields over the three steps f–h.
This deprotection[14] was also observed with KCN in dimeth-
yl sulfoxide (DMSO), albeit in lower yield. The formation
of ynamides 1d–f could be achieved under both Witulkiꢂs
and Hsungꢂs[15] conditions using 7 or 12,[16] respectively, in
low to moderate yields. However, both types of reaction al-
Results and Discussion
The synthesis of precursors 1 was achieved in seven or eight
steps (Schemes 3–5). We chose to introduce the fragile yna-
mide fragment at the last moment in each case. Compounds
1a–c exhibit two aliphatic nitrogen tethers with orthogonal
protecting groups for subsequent selective deprotection and
potential functionalization (Scheme 3, tosyl and carbobenzy-
loxy). 3-Butynol and 4-pentynol were protected as tetrahy-
dropyranyl (THP) ethers (a, Z=THP), alkylated at the
alkyne through deprotonation with BuLi and subsequent ad-
dition of p-formaldehyde (b), and activated as mesylate (c,
leaving group (LG)=Ms, 3a) or tosylate (LG=Ts, 3b). On
the other hand, 2-butyne-1,4-diol was monoprotected as a si-
lylated ether (d, Z=tert-butyldimethylsilyl (TBDMS)) and
subsequently tosylated (e, LG=Ts, 3c). Ynenitriles of type
5 were formed next by substitution of the propargylic mesy-
lates or tosylates by the amine 4[9] deprotonated by NaH (f).
After removal of the protecting group Z (g), the third nitro-
gen atom was introduced by Mitsunobu reactions with
Scheme 3. Synthesis of the precursors 1a–c from 3a (n=3, Z=THP,
LG=Ms), 3b (n=2, Z=THP, LG=Ts), and 3c (n=1, Z=TBDMS,
LG=Ts). Reagents and conditions: a) PTSA·H2O (1 mol%), dihydropyr-
an (DHP) (1.1 equiv), CH2Cl2, 08C!RT, 24 h; b) BuLi (1.3 equiv), p-
formaldehyde (6 equiv), THF, ꢀ788C!RT, overnight, 81% (n=3) and
87% (n=2), over two steps; c) 3a: MsCl (1.5 equiv), Et3N (1.4 equiv),
CH2Cl2, 08C !RT, overnight, 81%; 3b: TsCl (3.15 equiv), KOH
(3.06 equiv), Et2O, overnight, 85%; d) NaH (1.0 equiv), tert-butyldime-
thylsilyl chloride (TBDMSCl) (1.0 equiv), THF, RT, 4 h, 54%; 3c:
e) TsCl (1.2 equiv), KOH (10 equiv), Et2O, RT, 1 h, 68%; f) n=3:
KHMDS (1.1 equiv), TBAI (0.1 equiv), 4 (1.1 equiv), THF, RT, 2 h; n=2
Scheme 4. Synthesis of the precursors 1d–f from 9d (n=3, m=1, Z=
THP), 9e (n=3, m=2, Z=EE), and 9 f (n=2, m=1, Z=Ts). Reagents
and conditions: a) Standard protection with m=1 (Z=THP)[17] and m=
2 (Z=EE);[18] b) see ref. [19], 51% (9d) and 98% (9e); c) pyridine
(5 equiv), TsCl (2.5 equiv), CH2Cl2, 08C!RT, 18 h, 79%; d) BuLi
(1.2 equiv), ethylene oxide (3 equiv), BF3·OEt2 (1.2 equiv), THF, ꢀ788C,
2 h, 46% (9 f); e) PPh3 (1.1 equiv), DIAD (1.0 equiv), TsNHBoc
(1.0 equiv), THF, 08C!RT, 3.5 h, 68% (10d), 76% (10e), and 53%
(10 f); f) for 10d–e: PTSA·H2O (0.01 equiv), MeOH, RT, overnight;
g) for 10d–e: MsCl (1.5 equiv), Et3N (1.4 equiv), CH2Cl2, 08C!RT, over-
night; h) for 10d–e: NaCN (6 equiv), DMF, 808C, 24 h, 81% (11d) and
69% (11e) over three steps, or for 10 f: KCN (2 equiv), DMSO, 908C,
overnight, 45% (11 f); i) KHMDS (1.1 equiv), 7 (1.25 equiv), toluene,
808C, 24 h, 45% (1d) and 30% (1e), or K2CO3 (2 equiv), 1,10-phenan-
throline (0.2 equiv), CuSO4·5H2O (0.1 equiv), 12 (1.0 equiv), toluene,
608C, 36 h, 19% (1 f).
and n=1: NaH (1.1 equiv),
4 (1.1 equiv), DMF, RT, overnight;
g) PTSA·H2O (4 mol%), MeOH, 20 h, 91% (5a) and 85% (5b), over
two steps, or TBAF (1.3 equiv), THF, RT, 12 h, 68% (5c), over two
steps; h) PPh3 (1.1 equiv), DIAD (1.0 equiv), TsNHBoc (1.0 equiv), THF,
08C!RT, 3.5 h, 92% (6a), 88% (6b), and 82% (6c); i) PhOH
(70 equiv), TMSCl (23 equiv), CH2Cl2, RT, 2 h, 92% (n=3) and 38%
(n=2), or TFA (3 equiv), CH2Cl2, MW, 1008C, 20 min, 69% (n=1);
j) BuLi (1.01 equiv), THF, ꢀ788C!RT, 15 min; 7 (1.2 equiv), toluene,
708C, 2 h, 31 % (1a) and 45% (1b), or KHMDS (1.0 equiv),
(1.2 equiv), toluene, 408C, 34 % (1c).
7
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Chem. Eur. J. 2009, 15, 2129 – 2139

Tricyclic Fused 3-Aminopyridines
FULL PAPER
lowed the recovery of the unreacted starting material, which
could be submitted again to another coupling to eventually
yield the precursors for the cyclizations in reasonable
amounts.
We used a similar approach to synthesize precursors 1g
and 1h (Scheme 5, see Experimental Section for details).
Scheme 6. Tricyclic pyridines prepared by [2+2+2] cycloaddition (the
frameworks discussed in the text are highlighted).
tion of the four-membered ring required prolonged heating,
even with [CpCoACHTUNRGTNE(UNG C2H4)2] as catalyst. Products 2d–f, which
were all formed in excellent yields using method A,[23] are
unique examples of 2,3,6,7,8,9-hexahydro-1H-cyclopenta[f]-
AHCTUNGTREG[NNUN 1,7]naphthyridine (2d), -cyclopentapyrrolopyridine (2 f),
and octahydro-benzonaphthyridine (2e). The presence of
ester functionalities was tolerated during the formation of
2g (Table 1, entry 7, 76% yield). Finally, the cyclization of
1h, which has an oxygen tether, proved also successful
(Table 1, entry 8, 62% yield), although it was necessary in
this case to use up to 30 mol% of catalyst. Product 2h is the
Scheme 5. Synthesis of the precursors 1g and 1h (E=CO2Me).
The cyclizations were carried out with CpCoACHTNUTRGNEUNG(C2H4)2
(method A), which turns over already at room or lower tem-
perature,[20] or with CpCo(CO)2 (method B), which usually
requires heat and visible light to be active (Table 1 and
Scheme 6).[2g,21] Gratifyingly, both methods led to successful
cycloadditions of precursors 1a–h with the following details:
Compound 2a, which displays a novel framework of type
first
[1,7]naphthyridine.
An apparently simple and flexible way to functionalize
example
of
1,3,6,7,8,9-hexahydrofuroACHTUNGTRENNUNG[3,4-f]-
AHCTUNGTRENNUNG
the products would be to deprotect the amino groups and to
couple them with other organic moieties. This should be par-
ticularly straightforward, even in the case of the bis-amino
derivatives 2a–c, because we took care to introduce orthog-
onal protecting groups. Another opportunity lies in the silyl
group, which, in principle, can be substituted by an aryl or
vinyl group under Hiyama cross-coupling conditions.[24] This
seems quite challenging because unactivated trialkylsilyl
groups are usually poorly reactive, and besides, Hiyama cou-
plings of silylated pyridines are rare.[25] In view of the recent
work of Philippe Gros and co-workers, who showed that the
incorporation of chloro, fluoro, or methoxy substituents on
the pyridine ring of pyridyltrimethylsilanes allows efficient
Hiyama cross-couplings,[25a] we reasoned that our products,
which bear a nitrogen substituent, could also be valuable
partners for such transformations. Gratifyingly, under the
same experimental procedure, we were able to substitute
the trimethylsilyl group by a p-methoxybenzene group in
good yield (Scheme 7). The biaryl system 13 was obtained at
room temperature in an unoptimized 77% yield.
2,3,6,7,8,9-hexahydro-1H-pyrroloACTHNUTRGENN[GU 3,4-f]HCATUNGTRENN[UGN 1,7]naphthyridine
(highlighted in Scheme 6), was obtained in high yield with
each catalyst (Table 1, entry 1). Tricyclic product 2b
(Table 1, entry 2), which was obtained in 76 and 77% yield,
respectively, exhibits the basic skeleton of many derivatives
that are, however, all benzocondensed or oxidized as car-
bonyls at the benzylic positions. Product 2c (Table 1,
entry 3), which was obtained in 50 and 55% yield, respec-
tively, seems to be the first example of a stable 1,2-dihydro-
1H-azetoACHTUNGTRENNUNG
[3,4-c]pyridine.[22] In this specific case, the forma-
Table 1.
Entry
ACHTUNGTRENNUNG[2+2+2] cycloadditions of the precursors 1a–h.
Substrate
n
X
Product
Yield [%][a,b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
3
2
1
3
3
2
3
3
NCbz
NCbz
NCbz
CH2
2a
2b
2c
2d
2e
2 f
2g
2h
93[d] (91)[e]
76[d] (77)[e]
50[f] (55)[d]
100[c]
A
100[c]
90[c]
C
A
76[f]
O
62[g]
Conclusion
[a] Isolated yields corresponding to method A: [CpCoACHTUNRGTNEUNG(C2H4)2], THF, RT,
1 h. [b] In parentheses, isolated yields corresponding to method B:
[CpCo(CO)2], xylenes, reflux, hn, 1 h. Catalyst loads to reach full conver-
sion of the substrate: [c] 5 mol%; [d] 10 mol%; [e] 15 mol%;
[f] 20 mol%; [g] 30 mol%.
We have developed an expedient method for the synthesis
of tricyclic fused 2-trimethylsilyl-3-aminopyridines by unpre-
cedented intramolecular [2+2+2] cycloadditions between
Chem. Eur. J. 2009, 15, 2129 – 2139
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2131

C. Aubert, M. Malacria et al.
(44 mL) under Ar, followed after 15 min by 3a (1.28 g, 4.63 mmol). After
1 h, the reaction mixture was quenched with strd aq. NH4Cl, extracted
with Et2O, washed with brine, dried over MgSO4, filtered and concentrat-
ed under reduced pressure to afford a brown oil in quantitative yield
used without further purification. Rf =0.57 (CH2Cl2/Et2O 96:4); 1H NMR
(400 MHz, CDCl3): d=1.56–1.62 (m, 4H), 1.67–1.75 (m, 1H), 1.77–1.85
(m, 3H), 2.34 (tt, J=7.1, 1.9 Hz, 2H), 3.43–3.53, (m, 2H), 3.78–3.88 (m,
2H), 4.20–4.27 (m, 2H), 4.29–4.39 (m, 2H), 4.57–4.61 (m, 1H), 5.20 (s,
2H), 7.32–7.41 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=15.6
(CH2), 19.6 (CH2), 25.4 (CH2), 28.6 (CH2), 30.7 (CH2), 34.0/34.3 (CH2),
37.0/37.2 (CH2), 62.3 (CH2), 65.8 (CH2), 68.5 (CH2), 73.0 (C), 86.2/86.4
(C), 98.8 (CH), 115.4 (C), 128.1 (CH), 128.5 (CH), 128.6 (CH), 135.5 (C),
154.2/154.8 ppm (C); IR (neat): n˜ =3090, 3064, 3033, 2941, 2869, 2284,
Scheme 7. Hiyama cross-coupling between 2g (E=CO2Me) and p-iodo-
anisole.
2228, 1708, 1031 cmꢀ1
.
Step g: 4.1 g (11.07 mmol) of the product obtained after step f and p-tolu-
ene sulfonic acid (PTSA·H2O) (0.29 g, 1.52 mmol) were stirred in MeOH
(200 mL) for 20 h. The reaction mixture was quenched with strd aq.
NaHCO3, extracted with Et2O, washed with brine, dried over MgSO4, fil-
tered and concentrated under reduced pressure. The crude was purified
by CC (CH2Cl2 to CH2Cl2/Et2O 9:1) to afford 5a as a colorless oil
(2.88 g, 91%). Rf =0.30 (CH2Cl2/Et2O 4:1); 1H NMR (400 MHz, CDCl3):
d=1.70 (quint, J=6.5 Hz, 2H), 2.29 (tt, J=6.5, 2.1 Hz, 2H), 2.60 (brs,
1H), 3.64 (t, J=6.5 Hz, 2H), 4.17 (brs, 2H), 4.28 (brs, 2H), 5.16 (s, 2H),
7.30–7.35 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=15.1 (CH2),
30.9 (CH2), 34.3/34.6 (CH2), 37.3 (CH2), 61.1 (CH2), 68.5 (CH2), 73.2 (C),
86.2 (C), 115.6 (C), 128.1 (CH), 128.5 (CH), 128.6 (CH), 135.5 (C), 154.3/
154.9 ppm (C); IR (neat): n˜ =3400, 3064, 3033, 2947, 2877, 2188,
1703 cmꢀ1; HRMS: m/z: calcd for [C16H18N2O3Na]+: 309.12096; found:
309.12060.
ynamides, nitriles, and alkynes. Interestingly, most of these
compounds display basic skeletons that are new (or rare)
and most probably very difficult to prepare by conventional
methods. Although the formation of the ynamides implies
the introduction of a trimethylsilyl group, we turned this
into an advantage by achieving a Hiyama cross-coupling.
This aspect is under active development in our laboratories,
in view of preparing compounds of biological interest.
Experimental Section
6a: Compound 5a (2.50 g, 8.73 mmol) in THF (40 mL) and PPh3 (2.30 g,
8.75 mmol) were successively added to a solution of TsNHBoc[26] (2.39 g,
8.82 mmol) in THF (35 mL) under Ar at 08C, followed by the dropwise
addition over 1 h of DIAD (1.78 g, 8.80 mmol) in THF (20 mL) with a sy-
ringe pump. After 4 h (TLC monitoring), SiO2 was added and the solvent
removed under reduced pressure. Purification by CC (PE/CH2Cl2 2:8 to
pure CH2Cl2) afforded 6a as a pale-yellow oil (2.57 g, 55%). Rf =0.50
(PE/CH2Cl2 2:8); 1H NMR (400 MHz, CDCl3): d=1.34 (s, 9H), 2.00
(quint, J=7.1 Hz, 2H), 2.32 (t, J=7.1 Hz, 2H), 2.45 (s, 3H), 3.93 (t, J=
7.1 Hz, 2H), 4.23–4.29 (m, 2H), 4.29–4.46 (m, 2H), 5.21 (s, 2H), 7.32 (d,
J=8.3 Hz, 2H), 7.35–7.42 (m, 5H), 7.78 ppm (d, J=8.3 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=16.2 (CH2), 21.6 (CH3), 27.9 (CH3), 28.8
(CH2), 34.0/34.3 (CH2), 36.9/37.1 (CH2), 46.2 (CH2), 68.5 (CH2), 73.6 (C),
84.4 (C), 85.3/85.5 (C), 115.6 (C), 127.8 (CH), 128.2 (CH), 128.5 (CH),
128.6 (CH), 129.3 (CH), 135.5/135.6 (C), 137.3 (C), 144.2 (C), 150.9 (C),
154.2/154.8 ppm (C); IR (neat): n˜ =3065, 3033, 2976, 2933, 2870, 2226,
General methods: Glassware was oven-dried prior to use. Anhydrous
THF was obtained by distillation over sodium/benzophenone under ni-
trogen and used freshly distilled. Toluene and xylenes were distilled from
NaK2.8 amalgam; CH2Cl2 from CaH2; DMF from MgSO4. Reagents that
are commercially available were used as received. NMR spectra were re-
corded by using either a Bruker Avance 400 spectrometer fitted with a
QNP probe 13C/19F/31P/1H or a Bruker ARX 200 spectrometer fitted with
a dual 13C/1H probe. 1H NMR spectra are referenced at 7.26 ppm and
13C NMR spectra are referenced at 77.16 ppm for CDCl3. Chemical shifts
are given in ppm. When possible, 1H and 13C signals were assigned
mostly on the basis of distortion enhancement by polarization transfer
(DEPT)- and 2D-NMR (COSY, HMBC) experiments. In the description
of the 13C NMR spectra, a number at the beginning of the information in
parentheses refers to accidentally isochronous carbons. Due to the coex-
1
istence of rotamers, some H and 13C signals are doubled. The two chemi-
1713, 1351, 1153 cmꢀ1
;
HRMS: m/z: calcd for [C28H33N3O6NaS]+:
cal shifts are given, separated by a slash. IR spectra were recorded by
using a Tensor 27 (ATR diamond) Bruker spectrometer. IR data is re-
ported as characteristic bands (cmꢀ1). Melting points were recorded by
using a Stuart Scientific smp3 apparatus and are uncorrected. Purifica-
tions were achieved by performing column chromatography (CC) on
silica gel (40–63 mm). Microwave reactions were performed by using a Bio-
tage Iniator Microwave Synthetizer 2.0. TLC was performed on silica gel
60 F254 from Merck.
562.19823; found: 562.19765.
1a: Step i: Compound 6a (0.118 g, 0.219 mmol) and a solution of trime-
thylsilyl chloride (TMSCl) (0.550 g, 5.06 mmol) in CH2Cl2 (1.3 mL) were
successively added to a solution of PhOH (1.45 g, 15.44 mmol) in CH2Cl2
(4 mL) under Ar. After 2 h, the reaction mixture was diluted with
CH2Cl2, quenched with strd aq. NaHCO3, washed with brine, dried over
MgSO4, filtered and concentrated under reduced pressure to afford an
oil. Purification of the crude by CC (CH2Cl2 to CH2Cl2/Et2O 1:1) afford-
ed a colorless oil (0.089 g, 92%). Rf =0.23 (CH2Cl2/Et2O 96:4); 1H NMR
(400 MHz, CDCl3): d=1.66 (quint, J=6.8 Hz, 2H), 2.24 (t, J=6.8 Hz,
2H), 2.40 (s, 3H), 2.97–3.06 (m, 2H), 4.17 (brs, 2H), 4.28 (brs, 2H), 5.18
(s, 2H), 5.38 (t, J=6.2 Hz, 1H), 7.28 (d, J=8.2 Hz, 2H), 7.30–7.37 (m,
5H), 7.75 ppm (d, J=8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=15.8
(CH2), 21.5 (CH3), 28.1 (CH2), 34.3/34.7 (CH2), 37.3 (CH2), 41.9 (CH2),
68.5 (CH2), 73.9 (C), 85.3 (C), 115.7 (C), 127.1 (CH), 128.2 (CH), 128.5
(CH), 128.6 (CH), 129.8 (CH), 135.5 (C), 136.9 (C), 143.4 (C), 154.3/
154.8 ppm (C); IR (neat): n˜ =3274, 3064, 3033, 2946, 2872, 2253, 1704,
1325, 1156 cmꢀ1; HRMS: m/z: calcd for [C23H25N3O4NaS]+: 462.14580;
found: 462.14636.
4: 2-Aminoacetonitrile hydrogenosulfate (41.0 g, 265.94 mmol) was
added at 08C to a solution of N-benzyloxycarboxysuccinimide (60.0 g,
240.75 mmol) in CH2Cl2 (1.5 L) and Et3N (56.7 g, 560.33 mmol). After
warming for 12 h to Room temperature, the mixture was diluted with
Et2O, quenched with 1n HCl, extracted with CH2Cl2, washed with brine,
dried over MgSO4, filtered and concentrated under reduced pressure to
afford a pale yellow solid (43.2 g, 94%). Rf =0.30 (PE/EtOAc 7:3); m.p.
62.38C; 1H NMR (200 MHz, CDCl3): d=4.07 (d, J=6.2 Hz, 2H), 5.14 (s,
2H), 5.41 (brs, 1H), 7.35 ppm (s, 5H); 13C NMR (50 MHz, CDCl3): d=
29.6 (CH2), 67.9 (CH2), 116.3 (C), 128.5 (CH), 128.7 (CH), 128.8 (CH),
135.6 (C), 155.8 ppm (C); IR (neat): n˜ =3324, 1701, 1512, 1244 cmꢀ1
HRMS: m/z: calcd for [C10H10N2O2Na]+: 213.06345; found: 213.06322.
;
Step j: BuLi (1.9m in hexanes, 360 mL, 0.682 mmol) was added to a solu-
tion of the product obtained after step i (0.297 g, 0.676 mmol) in THF
(12 mL) at ꢀ788C under Ar in a Schlenk tube. After warming to room
5a: Step f: Potassium hexamethyldisilazane (KHMDS) (0.5m in toluene,
10.5 mL, 5.26 mmol) was added to a solution of 4 (967 mg, 5.08 mmol)
and tetrabutylammonium iodide (TBAI) (171 mg, 0.46 mmol) in THF
2132
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 2129 – 2139

Tricyclic Fused 3-Aminopyridines
FULL PAPER
temperature, the yellow solution was concentrated under reduced pres-
sure to give a solid directly diluted in toluene (12 mL) and warmed to
708C (bath temperature). After 10 min, iodonium salt 7[27] (0.367 g,
0.815 mmol) was added in portions over 5 min. After 3 h, SiO2 was
added, the solvent was removed under reduced pressure, and the crude
material purified by CC (pentane/Et2O 1:1) to afford 1a as a yellow oil
(160 mg, 45%). Rf =0.70 (pentane/Et2O 1:1); 1H NMR (400 MHz,
CDCl3): d=0.17 (s, 9H), 1.86 (q, J=6.7 Hz, 2H), 2.31 (t, J=6.7 Hz, 2H),
2.47 (s, 3H), 3.41 (t, J=6.7 Hz, 2H), 4.27 (brs, 2H), 4.39 (brs, 2H), 5.22
(s, 2H), 7.32–7.37 (m, 7H), 7.79 ppm (d, J=8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=0.0 (CH3), 15.6 (CH2), 21.6 (CH3), 26.3 (CH2),
34.0/34.4 (CH2), 37.0 (CH2), 49.8 (CH2), 68.4 (CH2), 73.3 (C), 73.9 (C),
84.9 (C), 94.6 (C), 115.5 (C), 127.7 (CH), 128.1 (CH), 128.4 (CH), 128.5
(CH), 129.6 (CH), 134.0 (C), 135.4 (C), 144.7 (C), 154.2/154.7 ppm (C);
IR (neat): n˜ =3065, 3033, 2956, 2157, 1710, 1363, 1168, 840 cmꢀ1; HRMS:
m/z: calcd for [C28H33N3O4NaSSi]+: 558.18532; found: 558.18530.
154.3/154.8 ppm (C); IR (neat): n˜ =3429, 3033, 2946, 2885, 2227,
1702 cmꢀ1; HRMS: m/z: calcd for [C15H16N2O3Na]+: 295.10531; found:
295.10571.
6b: Compound 5b (3.68 g, 13.53 mmol) in THF (40 mL) and PPh3
(3.59 g, 13.68 mmol) were successively added to a solution of TsNHBoc
(3.68 g, 13.85 mmol) in THF (80 mL) under Ar at 08C, followed by the
dropwise addition over 2 h of DIAD (2.79 g, 13.79 mmol) in THF
(20 mL) with a syringe pump. After 3 h, SiO2 was added and the solvent
removed under reduced pressure. Purification by CC (PE/CH2Cl2 2:8 to
CH2Cl2/Et2O 9:1) afforded a pale-yellow oil (6.23 g, 88%). Rf =0.62
(CH2Cl2/Et2O 94:6); 1H NMR (400 MHz, CDCl3): d=1.34 (s, 9H), 2.45
(s, 3H), 2.70 (brs, 2H), 4.00 (brs, 2H), 4.24–4.27 (m, 2H), 4.35–4.39 (m,
2H), 5.20 (s, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.35–7.45 (m, 5H), 7.78 ppm
(d, J=8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=20.1 (CH2), 21.6
(CH3), 27.8 (CH3), 34.1/34.4 (CH2), 36.9/37.1 (CH2), 45.2 (CH2), 68.5
(CH2), 75.3 (C), 82.7/82.9 (C), 84.7 (C), 115.5 (C), 127.8 (CH), 128.2
(CH), 128.5 (CH), 128.6 (CH), 129.3 (CH), 135.5 (C), 137.2 (C), 144.4
(C), 150.7 (C), 154.3/154.7 ppm (C); IR (neat): n˜ =2980, 2933, 1714, 1352,
2a: Method A: Compound 1a (83 mg, 0.158 mmol) in THF (2 mL) was
added to [CpCo
ACHTUNGTRENNUNG
1154 cmꢀ1
.
tube. After 3 h (TLC monitoring), some [CpCoACHTUNGTRENNUNG
(0.60 mg, 0.003 mmol). After a further 2 and then 12 h, the same addition
was carried out with 2.0 mg (0.011 mmol) and 1.5 mg (0.008 mmol), re-
spectively, of [CpCoACHTUNGTRENNUNG(C2H4)2]. SiO2 was added and the solvent was re-
1b: Step i: A solution of 6b (6.25 g, 11.850 mmol) in CH2Cl2 (80 mL) and
a solution of TMSCl (34.8 g, 320.3 mmol) in CH2Cl2 (160 mL) were suc-
cessively added by using a cannula to a solution of PhOH (93.0 g,
988.2 mmol) in CH2Cl2 (100 mL) under Ar. After 3 h, the reaction mix-
ture was diluted with CH2Cl2, quenched with strd aq. NaHCO3, washed
with brine, dried over MgSO4, filtered and concentrated under reduced
pressure. After two successive CC (CH2Cl2/PE 9:1 to CH2Cl2/Et2O 7:3),
the resulting oil was washed with 10% aq. NaOH to afford a colorless oil
(2.52 g, 38%). Rf =0.31 (CH2Cl2/Et2O 95:5); 1H NMR (400 MHz,
CDCl3): d=2.35 (brs, 5H), 3.05 (brs, 2H), 4.12 (brs, 2H), 4.24 (brs, 2H),
5.14 (s, 2H), 5.78 (brs, 1H), 7.23–7.33 (m, 7H), 7.74 ppm (d, J=8.3 Hz,
2H); 13C NMR (100 MHz, CDCl3): d=20.3 (CH2), 21.5 (CH3), 34.6/34.8
(CH2), 37.3/37.4 (CH2), 41.6 (CH2), 68.6 (CH2), 75.3 (C), 82.9 (C), 115.8
(C), 127.0 (CH), 128.2 (CH), 128.5 (CH), 128.7 (CH), 129.8 (CH), 135.4
(C), 137.0 (C), 143.6 (C), 154.3/154.8 ppm (C); IR (neat): n˜ =3272, 3064,
moved under reduced pressure. Two successive CC of the crude material
(pentane/Et2O 3:7) afforded a white solid (77 mg, 93%). Method B:
[CpCo(CO)2] (38 mL, 0.029 mmol) was added to a refluxing solution of
1a (336 mg, 0.573 mmol) in degassed xylenes (12.0 mL) and the reaction
was irradiated (visible light, halogen lamp, 150 W) for 30 min. SiO2 was
added and the solvent was removed under reduced pressure. Two succes-
sive CC (PE/CH2Cl2/Et2O 5:4:1) of the material gave a white solid
(279 mg, 91%). Rf =0.31 (PE/Et2O 3:7); m.p. 133.68C; 1H NMR
(400 MHz, CDCl3): d=0.44/0.45 (2s, 9H), 1.21–1.29 (m, 1H), 1.43–1.54
(m, 1H), 1.69–1.79 (m, 1H), 2.10–2.33 (m, 1H), 2.42/2.43 (2s, 3H), 3.39–
3.47 (m, 1H), 4.08–4.16 (m, 1H), 4.50–4.65 (m, 2H), 4.75–4.90 (m, 2H),
5.20–5.35 (m, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.27–7.45 ppm (m, 7H);
13C NMR (100 MHz, CDCl3): d=0.0 (CH3), 20.7/20.8 (CH2), 21.3 (CH3),
21.7/21.8 (CH2), 44.8/44.9 (CH2), 48.9/49.2 (CH2), 52.7/53.0 (CH2), 66.8/
66.9 (CH2), 126.4/126.6 (C), 127.3/127.4 (CH), 127.8 (CH), 127.9 (CH),
128.2 (CH), 129.4 (CH), 135.9/136.0 (C), 136.2/136.3 (C), 137.3/137.4 (C),
137.6 (C), 143.6/143.7 (C), 154.3/154.8 (C), 155.0/155.2 (C), 168.1/
168.2 ppm (C); IR (neat): n˜ =3089, 3064, 3032, 2950, 2896, 1704, 1355,
1161, 840 cmꢀ1; HRMS: m/z: calcd for [C28H34N3O4SSi]+: 536.20338;
found: 536.20275.
3032, 2948, 2233, 1704, 1326, 1156 cmꢀ1
[C22H23N3O4NaS]+: 448.13015; found: 448.13002.
; HRMS: m/z: calcd for
Step j: BuLi (1.9m in hexanes, 330 mL, 0.633 mmol) was added to a solu-
tion of the product obtained after step i (0.270 g, 0.634 mmol) in THF
(12 mL) at ꢀ788C under Ar in a Schlenk tube. After warming to room
temperature the yellow solution was concentrated under reduced pres-
sure to give a solid that was directly diluted with toluene (12 mL) and
warmed to 708C (bath temperature). After 10 min, iodonium salt 7
(0.346 g, 0.768 mmol) was added in portions over 5 min. After 2 h, SiO2
was added, the solvent was removed under reduced pressure and the
crude material purified by CC (pentane/Et2O 1:1) to afford 1b as a
yellow oil (103 mg, 31%). Rf =0.70 (pentane/Et2O 1:1); 1H NMR
(400 MHz, CDCl3): d=0.18 (s, 9H), 2.47 (s, 3H), 2.57 (t, J=7.3 Hz, 2H),
3.47 (t, J=7.3 Hz, 2H), 4.21/4.24 (2s, 2H), 4.33/4.37 (2s, 2H), 5.22 (s,
2H), 7.30–7.40 (m, 7H), 7.79 ppm (d, J=8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=0.1 (CH3), 18.6 (CH2), 21.7 (CH3), 34.2/34.5
(CH2), 36.9/37.1 (CH2), 49.8 (CH2), 68.6 (CH2), 73.9 (C), 75.3 (C), 82.0/
82.1 (C), 94.2 (C), 115.5 (C), 127.7 (CH), 128.2 (CH), 128.5 (CH), 128.7
(CH), 129.7 (CH), 134.3 (C), 135.5 (C), 144.9 (C), 154.3/154.7 ppm (C);
5b: Step f: NaH (60 wt% in oil, 118 mg, 0.29 mmol) was added to a solu-
tion of 4 (56.1 mg, 0.029 mmol) in DMF (2 mL), followed after 15 min by
3b[28] (88 mg, 0.26 mmol). After 12 h, the reaction mixture was quenched
with strd aq. NH4Cl, extracted with Et2O, washed with brine, dried over
MgSO4, filtered and concentrated under reduced pressure to afford a
yellow oil (103 mg) in quantitative yield used without further purifica-
tion. Rf =0.03 (PE/Et2O 7:3); 1H NMR (400 MHz, CDCl3): d=1.49–1.85
(m, 6H), 2.50 (tt, J=6.9, 2.1 Hz, 2H), 3.48–3.57 (m, 2H), 3.78–3.89 (m,
2H), 4.24 (brs, 2H), 4.35 (brs, 2H), 4.61 (brs, 1H), 5.19 (s, 2H),
7.37 ppm (brs, 5H); 13C NMR (100 MHz, CDCl3): d=19.6 (CH2), 20.3
(CH2), 25.5 (CH2), 30.7 (CH2), 34.1/34.3 (CH2), 37.1 (CH2), 62.5 (CH2),
65.5 (CH2), 68.7 (CH2), 73.9 (C), 84.1 (C), 98.9 (CH), 115.5 (C), 128.3
(CH), 128.6 (CH), 128.7 (CH), 135.6 (C), 154.4/154.9 ppm (C); IR (neat):
n˜ =2942, 1709, 1237, 1032 cmꢀ1; HRMS: m/z: calcd for [C20H24N2O4Na]+:
379.16283; found: 379.16252.
IR (neat): n˜ =3066, 3034, 2958, 2899, 2157, 1712, 1366, 1169, 843 cmꢀ1
;
HRMS: m/z: calcd for [C27H31N3O4NaSSi]+: 544.16967; found: 544.16975.
2b: Method A: Compound 1b (94 mg, 0.180 mmol) in THF (1 mL) was
added to [CpCo
ACHTUNGTRENNUNG
Step g: The product obtained after step f (0.103 g, 0.289 mmol) and
PTSA·H2O (3.7 mg, 0.019 mmol) were stirred in MeOH (10 mL) for 20 h.
The reaction mixture was quenched with strd aq. NaHCO3, extracted
with Et2O, washed with brine, dried over MgSO4, filtered and concentrat-
ed under reduced pressure. The crude was purified by CC (CH2Cl2 to
CH2Cl2/Et2O 9:1) to afford 5b as a colorless oil (60 mg, 75%). Rf =0.23
(CH2Cl2/Et2O 7:3); 1H NMR (400 MHz, CDCl3): d=2.40 (t, J=6.2 Hz,
2H), 3.29 (brs, 1H), 3.65 (t, J=6.2 Hz, 2H), 4.16 (s, 2H), 4.25 (s, 2H),
5.14 (s, 2H), 7.28–7.34 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=
23.0 (CH2), 34.4/34.7 (CH2), 37.3/37.5 (CH2), 60.7 (CH2), 68.6 (CH2), 74.7
(C), 83.9 (C), 115.7 (C), 128.2 (CH), 128.5 (CH), 128.7 (CH), 135.4 (C),
tube. After 15 h (TLC monitoring), some [CpCoACHTUNGTRENNUNG
(1.70 mg, 0.009 mmol). After a further 3 h, SiO2 was added and the sol-
vent was removed under reduced pressure. CC of the crude material
(pentane/Et2O 3:7) afforded a white solid that was purified again by CC
(same eluent) to afford
a white solid (70 mg, 76%). Method B:
[CpCo(CO)2] (18 mL, 0.014 mmol) was added to a refluxing solution of
1b (145 mg, 0.278 mmol) in degassed xylenes (5.6 mL) and the reaction
irradiated (visible light, halogen lamp, 150 W) for 30 min. Some
[CpCo(CO)2] (18 mL, 0.014 mmol) was then added and the reaction was
irradiated while refluxing for 30 min. This operation was performed once
more and then SiO2 was added and the solvent removed under reduced
Chem. Eur. J. 2009, 15, 2129 – 2139
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2133

C. Aubert, M. Malacria et al.
pressure. Two successive CC (PE/CH2Cl2/Et2O 5:3:2) of the material
gave a white solid (117 mg, 77%). Rf =0.23 (PE/Et2O 7:3); m.p. 143.38C;
1H NMR (400 MHz, CDCl3): d=0.25 (s, 9H), 1.70–1.80 (m, 2H), 2.20 (s,
3H), 3.74–3.78 (m, 2H), 4.27/4.30 (2s, 2H), 4.61 (m, 2H), 5.00/5.04 (2s,
2H), 6.96 (d, J=8.3 Hz, 2H), 7.05–7.25 ppm (m, 7H); 13C NMR
(100 MHz, CDCl3): d=0.0 (CH3), 21.7 (CH3), 26.5 (CH2), 49.5/49.7
(CH2), 51.4 (CH2), 52.8/53.1 (CH2), 67.3/67.4 (CH2), 125.4 (C), 125.6 (C),
127.9 (CH), 128.2 (CH), 128.3 (CH), 128.6 (CH), 129.7 (CH), 133.7/133.9
(C), 136.6 (C), 138.9/139.1 (C), 144.6/144.9 (C), 154.7/155.2 (C), 155.9/
156.2 (C), 161.0/161.1 ppm (C); IR (neat): n˜ =3064, 3032, 2952, 2899,
2869, 1704, 1354, 1164 cmꢀ1; HRMS: m/z: calcd for [C27H32N3O4SSi]:
522.18773; found:522.18715.
Step j: KHMDS (227 mg, 1.080 mmol) was added under vigorous stirring
to a solution of the product obtained after step i (0.444 g, 1.080 mmol) in
toluene (20 mL) under Ar in a Schlenk tube. After 5 min, iodonium salt
7 (0.585 g, 1.300 mmol) was added and the reaction warmed to 408C
(bath temperature) for 1 h. SiO2 was added and the solvent was removed
under reduced pressure. CC of the crude material (CH2Cl2 to CH2Cl2/
Et2O 9:1) afforded 1c as a yellow oil (186 mg, 34%). Rf =0.55 (CH2Cl2);
1H NMR (400 MHz, CDCl3): d=0.18 (s, 9H), 2.46 (s, 3H), 4.14 (brs,
4H), 4.26 (t, J=1.9 Hz, 2H), 5.20 (s, 2H), 7.30–7.45 (m, 7H), 7.81 ppm
(d, J=7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=0.0 (CH3), 21.7
(CH3), 33.7/33.8 (CH2), 36.2/36.4 (CH2), 41.7 (CH2), 68.7 (CH2), 74.2 (C),
78.4/78.5 (C), 79.1/79.3 (C), 94.2 (C), 114.9 (C), 128.2 (CH), 128.6 (CH),
128.7 (CH), 129.5 (CH), 133.9 (C), 135.2 (C), 145.3 (C), 154.0/154.3 ppm
(C), one CHarom hidden; IR (neat): n˜ =3034, 2958, 2169, 1712, 1367, 1169,
841 cmꢀ1; HRMS: m/z: calcd for [C26H29N3O4NaSSi]+: 530.15402; found:
530.15363.
5c: Step f: NaH (60 wt% in oil, 32.1 mg, 0.802 mmol) was added to a so-
lution of 4 (156.5 mg, 0.823 mmol) in DMF (3 mL), followed after 15 min
by 3c[29] (294 mg, 0.829 mmol). After a further 12 h, the reaction mixture
was quenched with strd aq. NH4Cl, extracted with Et2O, washed with
brine, dried over MgSO4, filtered and concentrated under reduced pres-
sure. The crude was purified by CC (PE/EtOAc 9:1) to afford a yellow
oil (221 mg, 74%). 1H NMR (200 MHz, CDCl3): d=0.15 (s, 6H), 0.95 (s,
9H), 4.20–4.40 (m, 6H), 5.20 (s, 2H), 7.35–7.45 ppm (m, 5H); 13C NMR
(50 MHz, CDCl3): d=ꢀ7.4 (CH3), 13.8 (C), 20.7 (CH3), 35.8 (CH2), 36.1
(CH2), 53.0 (CH2), 69.9 (CH2), 79.5 (C), 82.3 (C), 114.9 (C), 127.3 (CH),
127.4 (CH), 128.7 (CH), 136.3 (C), 156.8 ppm (C); IR (neat): n˜ =2929,
2857, 1712, 1237, 834 cmꢀ1; HRMS: m/z: calcd for [C20H28N2O3NaSi]+:
395.17614; found: 395.17609.
2c: Method A: Compound 1c (30 mg, 0.059 mmol) in xylenes (0.8 mL)
was added to [CpCo
N
a
Schlenk tube. After 3 h (TLC monitoring), [CpCoACHTUNGTRENNUNG
(0.60 mg, 0.003 mmol). After a further 3 h, the reaction mixture was
poured onto silica and eluted (PE/Et2O 3:7) to afford a white solid
(17 mg, 50%). Method B: [CpCo(CO)2] (17 mL, 0.014 mmol) was added
to a refluxing solution of 1c (139 mg, 0.274 mmol) in degassed xylenes
(5.5 mL), and the reaction irradiated (visible light, halogen lamp, 150 W)
for 30 min. Some [CpCo(CO)2] (18 mL, 0.014 mmol) was then added and
the reaction irradiated while refluxing for 30 min, after which SiO2 was
added and the solvent removed under reduced pressure. Two successive
CC (PE/CH2Cl2/Et2O 5:3:2) of the crude material gave a white solid
(76 mg, 55%). Rf =0.25 (PE/CH2Cl2/Et2O 5:3:2); m.p. 79.38C; 1H NMR
(400 MHz, CDCl3): d=0.50/0.51 (2s, 9H), 2.39/2.40 (2s, 3H), 4.57 (s,
2H), 4.66/4.70 (m, 4H), 5.18/5.21 (2s, 2H), 7.22/7.25 (2d, J=8.1 Hz, 2H),
7.30–7.43 (m, 5H), 7.60/7.63 ppm (2d, J=8.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=0.0 (CH3), 22.8 (CH3), 49.7/50.0 (CH2), 53.7/54.0
(CH2), 62.0/62.1 (CH2), 68.4 (CH2), 124.4/124.6 (C), 129.1 (CH), 129.2
(CH), 129.3 (CH), 129.7 (CH), 131.0 (CH), 132.7 (C), 134.2/134.4 (C),
137.6 (C), 146.1 (C), 153.3 (C), 155.3 (C), 155.7/156.0 (C), 156.1/
Step g: The product obtained after step f (0.212 g, 0.564 mmol) and tetra-
butyl ammonium fluoride (TBAF) (1m in THF, 0.75 mL, 0.75 mmol)
were stirred in THF (10 mL) for 12 h. The reaction mixture was
quenched with water, extracted with Et2O, washed with brine, dried over
MgSO4, filtered and concentrated under reduced pressure. The crude was
purified by CC (CH2Cl2 to CH2Cl2/Et2O 4:1) to afford a yellow oil
(134 mg, 92%). Rf =0.34 (CH2Cl2/Et2O 4:1); 1H NMR (400 MHz,
CDCl3): d=3.02 (brs, 1H), 4.21–4.23 (m, 4H), 4.27 (brs, 2H), 5.16 (s,
2H), 7.31–7.35 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=34.5/34.8
(CH2), 37.2/37.3 (CH2), 50.8 (CH2), 68.7 (CH2), 78.4 (C), 84.6 (C), 115.6
(C), 128.3 (CH), 128.6 (CH), 128.7 (CH), 135.4 (C), 154.4/154.8 ppm (C);
156.4 ppm (C); IR (neat): n˜ =2923, 2871, 1706, 1358, 1167, 845 cmꢀ1
HRMS: m/z: calcd for [C26H30O4N3SSi]+: 508.17208; found: 508.17135.
;
IR (neat): n˜ =3064, 3032, 2924, 2865, 2252, 1701, 1497, 1450, 1014 cmꢀ1
.
6c: Compound 5c (1.36 g, 5.27 mmol) in THF (20 mL) and PPh3 (1.66 g,
6.32 mmol) were successively added to a solution of TsNHBoc (1.74 g,
6.41 mmol) in THF (30 mL) under Ar at 08C, followed by the dropwise
addition over 3 h of DIAD (1.28 g, 6.32 mmol) in THF (7 mL) with a sy-
ringe pump. After 7 h, SiO2 was added and the solvent removed under
reduced pressure. Purification by two successive CC (PE/CH2Cl2 2:8 to
pure CH2Cl2) afforded a colorless oil (2.35 g, 82%). Rf =0.28 (CH2Cl2);
1H NMR (400 MHz, CDCl3): d=1.35 (s, 9H), 2.45 (s, 3H), 4.33 (brs,
4H), 4.66 (t, J=1.6 Hz, 2H), 5.22 (s, 2H), 7.25–7.35 (m, 7H), 7.86 ppm
(d, J=7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.7 (CH3), 27.8
(CH3), 33.8/34.1 (CH2), 35.8 (CH2), 36.5/36.7 (CH2), 68.7 (CH2), 77.2 (C),
81.5/81.8 (C), 85.2 (C), 115.1 (C), 128.0 (CH), 128.2 (CH), 128.6 (CH),
128.7 (CH), 129.3 (CH), 135.3 (C), 136.6 (C), 144.7 (C), 150.2 (C),
154.6 ppm (C); IR (neat): n˜ =3066, 3033, 2982, 2935, 1716, 1356,
1147 cmꢀ1; HRMS: m/z: calcd for [C26H29N3O6NaS]+: 534.16693; found:
534.16646.
10d: PPh3 (0.559 g, 2.28 mmol) and TsNHBoc (0.585 g, 2.28 mmol) were
successively added to a solution of 9d[30] (0.487 g, 2.28 mmol) in THF
(11 mL) under Ar at 08C, followed by the dropwise addition over 1 h of
DIAD (0.45 mL, 2.28 mmol) with a syringe pump. After 3 h, SiO2 was
added and the solvent removed under reduced pressure. Purification by
CC (cyclohexane/EtOAc 85:5) afforded a colorless oil (0.72 g, 68%).
Rf =0.65 (cyclohexane/EtOAc 3:2); 1H NMR (400 MHz, CDCl3): d=1.33
(s, 9H), 1.49–1.56 (m, 4H), 1.76–1.81 (m, 4H), 1.93 (quint, J=7.0 Hz,
2H), 2.20–2.28 (m, 4H), 2.44 (s, 3H), 3.47–3.52 (m, 2H), 3.78–3.90 (m,
4H), 4.60 (brs, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.78 ppm (d, J=8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3): d=15.6 (CH2), 16.3 (CH2), 19.5
(CH2), 21.5 (CH3), 25.4 (CH2), 27.8 (CH3), 29.1 (CH2), 29.4 (CH2), 30.6
(CH2), 46.4 (CH2), 62.1 (CH2), 66.0 (CH2), 79.0 (C), 80.4 (C), 84.3 (C),
98.8 (CH), 127.9 (CH), 129.4 (CH), 137.5 (C), 144.2 (C), 151.0 ppm (C);
IR (neat): n˜ =2938, 1724, 1353, 1154 cmꢀ1
; HRMS: m/z: calcd for
[C25H39NO6NaS]+: 504.2396; found: 504.2409.
1c: Step i: A solution of 6c (2.35 g, 4.59 mmol) in CH2Cl2 (20 mL) and
freshly distilled TFA (1.06 mL, 13.8 mmol) was microwaved at 1008C for
20 min. The reaction mixture was then quenched with strd aq. NaHCO3,
extracted with CH2Cl2, washed with brine, dried over MgSO4, filtered,
concentrated under reduced pressure and purified by CC (CH2Cl2 to
11d: Step f: Compound 10d (0.716 g, 1.53 mmol) and PTSA·H2O
(3.0 mg, 0.016 mmol) were stirred in MeOH (3 mL) for 12 h. The reaction
mixture was quenched with strd aq. NaHCO3, extracted with CH2Cl2,
washed with brine, dried over MgSO4, filtered and concentrated under
reduced pressure to afford
a
colorless oil (0.42 g, 70%). 1H NMR
CH2Cl2/Et2O 95:5) to afford
a yellow oil (1.31 g, 69%). Rf =0.47
(CH2Cl2/Et2O 9:1); 1H NMR (400 MHz, CDCl3): d=2.38 (s, 3H), 3.79/
3.80 (2s, 2H), 3.99 (brs, 2H), 4.11 (brs, 2H), 5.15 (s, 2H), 5.54 (brs, 1H),
7.25–7.36 (m, 7H), 7.75 ppm (d, J=8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=21.5 (CH3), 32.9 (CH2), 34.2/34.5 (CH2), 36.8 (CH2), 68.7
(CH2), 77.7 (C), 80.5 (C), 115.5 (C), 127.4 (CH), 128.2 (CH), 128.6 (CH),
128.7 (CH), 129.7 (CH), 135.3 (C), 136.6 (C), 143.9 (C), 154.1/154.6 ppm
(C); IR (neat): n˜ =3263, 3090, 3064, 2982, 2957, 2926, 2871, 2253, 1705,
(200 MHz, CDCl3): d=1.32 (s, 9H), 1.73 (quint, J=6.3 Hz, 2H), 1.89–
1.96 (m, 2H), 2.20–2.31 (m, 4H), 2.43 (s, 3H), 3.77 (t, J=6.0 Hz, 2H),
3.90 (t, J=7.4 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 7.76 ppm (d, J=8.3 Hz,
2H), OH unobserved; 13C NMR (50 MHz, CDCl3): d=15.4 (CH2), 16.4
(CH2), 21.8 (CH3), 28.0 (CH3), 29.5 (CH2), 31.4 (CH2), 46.5 (CH2), 61.8
(CH2), 79.6 (C), 80.3 (C), 84.4 (C), 127.9 (CH), 129.4 (CH), 137.3 (C),
144.3 (C), 151.0 ppm (C); IR (neat): n˜ =3440, 2934, 1726, 1351, 1351,
1328, 1156 cmꢀ1
.
1154, 1153 cmꢀ1
.
2134
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 2129 – 2139

Tricyclic Fused 3-Aminopyridines
FULL PAPER
Step g: MsCl (0.170 mL, 2.199 mmol) was added dropwise to a solution
of the product obtained after step f (0.420 g, 1.099 mmol) and Et3N
(0.306 mL, 2.199 mmol) in CH2Cl2 (6 mL) at 08C. 12 h after warming to
room temperature, the reaction mixture was quenched with strd aq.
NaHCO3, extracted with CH2Cl2, washed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure to afford, after purifi-
cation by CC (PE/EtOAc 3:2), a colorless oil (0.492 g, 94%). 1H NMR
(400 MHz, CDCl3): d=1.32 (s, 9H), 1.91–1.95 (m, 4H), 2.24 (tt, J=7.0,
2.3 Hz, 2H), 2.33 (tt, J=6.7, 2.4 Hz, 2H), 2.44 (s, 3H), 3.02 (s, 3H), 3.90
(t, J=7.6 Hz, 2H), 4.37 (t, J=6.1 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H),
7.76 ppm (d, J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=15.1
(CH2), 16.4 (CH2), 21.8 (CH3), 28.0 (CH3), 28.4 (CH2), 29.4 (CH2), 37.3
(CH3), 46.5 (CH2), 68.9 (CH2), 78.7 (C), 80.4 (C), 84.4 (C), 127.9 (CH),
129.4 (CH), 137.5 (C), 144.3 (C), 151.0 ppm (C); IR (neat): n˜ =2936,
(10 mL) under Ar at 08C, followed by the dropwise addition over 1 h of
DIAD (0.52 mL, 2.13 mmol) with a syringe pump. After 2 h, SiO2 was
added and the solvent removed under reduced pressure. Purification by
CC (PE/EtOAc 9:1) afforded a colorless oil (0.77 g, 76%). Rf =0.62 (PE/
EtOAc 9:1); 1H NMR (200 MHz, CDCl3): d=1.18 (t, J=7.0 Hz, 3H),
1.29 (d, J=5.0 Hz, 3H), 1.33 (s, 9H), 1.51–1.75 (m, 4H), 1.91 (t, J=
7.5 Hz, 2H), 2.15–2.24 (m, 4H), 2.43 (s, 3H), 3.41–3.70 (m, 4H), 3.87 (t,
J=7.5 Hz, 2H), 4.66 (q, J=5.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H),
7.77 ppm (d, J=8.0 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=14.3 (CH2),
15.5 (CH2), 16.5 (CH2), 20.0 (CH3), 21.8 (CH3), 25.9 (CH3), 28.0 (CH2),
29.2 (CH3), 29.6 (CH2), 46.6 (CH2), 60.9 (CH2), 64.8 (CH2), 78.0 (C), 80.7
(C), 84.6 (C), 99.6 (CH), 128.0 (CH), 129.4 (CH), 137.4 (C), 144.2 (C),
151.0 ppm (C); IR (neat): n˜ =2978, 1726, 1354, 1154 cmꢀ1; HRMS: m/z:
calcd for [C25H39NO6NaS]+: 504.2396; found: 504.2409.
1724, 1349, 1153 cmꢀ1
.
11e: Step f: Compound 10e (0.775 g, 1.611 mmol) and PTSA·H2O
(3.0 mg, 0.016 mmol) were stirred in MeOH (4 mL) for 12 h. The reaction
mixture was quenched with strd aq. NaHCO3, extracted with CH2Cl2,
washed with brine, dried over MgSO4, filtered and concentrated under
reduced pressure to afford a pale yellow oil (0.60 g, 91%). Rf =0.23 (cy-
clohexane/EtOAc 7:3); 1H NMR (200 MHz, CDCl3): d=1.33 (s, 9H),
1.55–1.60 (m, 3H), 1.68–1.75 (m, 2H), 1.93 (quint, J=7.0 Hz, 2H), 2.18–
2.26 (m, 4H), 2.43 (s, 3H), 3.66 (t, J=6.6 Hz, 2H), 3.91 (t, J=7.7 Hz,
2H), 7.29 (d, J=8.1, Hz, 2H), 7.76 ppm (d, J=8.1 Hz, 2H); 13C NMR
(50 MHz, CDCl3): d=16.5 (CH2), 18.7 (CH2), 21.8 (CH3), 25.3 (CH2),
28.0 (CH3), 29.5 (CH2), 32.0 (CH2), 46.7 (CH2), 62.7 (CH2), 79.2 (C), 80.8
(C), 84.4 (C), 127.9 (CH), 129.4 (CH), 137.5 (C), 144.3 (C), 151.1 ppm
Step h: NaCN (0.287 g, 5.870 mmol) was added to the product obtained
after step g (0.447 g, 0.978 mmol) in DMF (10 mL). The mixture was
warmed to 808C for 24 h, diluted with Et2O and washed with water,
brine, dried over MgSO4, filtered and concentrated under reduced pres-
sure. Purification of the crude material by CC (PE/EtOAc 9:1) afforded
11d as a yellow oil (0.283 g, 80%). Rf =0.35 (PE/EtOAc 9:1); 1H NMR
(400 MHz, CDCl3): d=1.63 (q, J=7.0 Hz, 2H), 1.77 (q, J=7.0 Hz, 2H),
2.18 (tt, J=7.0, 2.3 Hz, 2H), 2.27 (tt, J=7.0, 2.3 Hz, 2H), 2.41 (s, 3H),
2.43 (t, J=7.0 Hz, 2H), 3.01 (q, J=6.4 Hz, 2H), 4.93 (t, J=6.4 Hz, 1H),
7.30 (d, J=8.0 Hz, 2H), 7.73 ppm (d, J=8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=16.0 (CH2), 16.2 (CH2), 17.9 (CH2), 21.6 (CH3),
24.7 (CH2), 28.5 (CH2), 42.3 (CH2), 78.6 (C), 80.7 (C), 119.5 (C), 127.2
(CH), 129.8 (CH), 137.0 (C), 143.5 ppm (C); IR (neat): n˜ =3268, 2933,
(C); IR (neat): n˜ =3389, 2934, 1724, 1350, 1153 cmꢀ1
.
Step g: MsCl (0.226 mL, 2.93 mmol) was added dropwise to a solution of
the product obtained after step f (0.600 g, 1.47 mmol) and Et3N
(0.409 mL, 2.93 mmol) in CH2Cl2 (7 mL) at 08C. 12 h after warming to
room temperature, the reaction mixture was quenched with strd aq.
NaHCO3, extracted with CH2Cl2, washed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure to afford, after purifi-
cation by CC (cyclohexane/EtOAc 85:15) a colorless oil (0.496 g, 70%).
Rf =0.52 (cyclohexane/EtOAc 7:3); 1H NMR (200 MHz, CDCl3): d=1.32
(s, 9H), 1.64 (brs, 2H), 1.85–1.92 (m, 4H), 2.23 (t, J=6.0 Hz, 4H), 2.44
(s, 3H), 2.99 (s, 3H), 3.89 (t, J=7.6 Hz, 2H), 4.26 (t, J=6.3 Hz, 2H), 7.30
(d, J=8.4 Hz, 2H), 7.76 ppm (d, J=8.4 Hz, 2H); 13C NMR (50 MHz,
CDCl3): d=16.5 (CH2), 18.3 (CH2), 21.8 (CH3), 24.9 (CH2), 28.0 (CH3),
28.3 (CH2), 29.5 (CH2), 37.5 (CH3), 46.6 (CH2), 69.9 (CH2), 79.7/79.9 (C),
106.4 (C), 114.1 (C), 127.9 (CH), 129.4 (CH), 137.5 (C), 144.3 (C),
1662, 1323, 1155 cmꢀ1
.
1d: KHMDS (0.5m in toluene, 720 mL, 362 mmol) was added under vigo-
rous stirring to a solution of 11d (0.100 g, 0.323 mmol) in toluene under
Ar in a Schlenk tube. After 10 min, iodonium salt 7 (0.185 g, 0.411 mmol)
was added and the reaction mixture heated at 808C (bath temperature)
for 24 h. SiO2 was added and the solvent was removed under reduced
pressure. CC of the crude material (PE/EtOAc 8:2) afforded a yellow oil
(60 mg, 45%). Rf =0.60 (PE/EtOAc 3:2); 1H NMR (200 MHz, CDCl3):
d=0.15 (s, 9H), 1.76–1.87 (m, 4H), 2.18–2.37 (m, 4H), 2.45 (s, 3H), 2.48–
2.57 (m, 2H), 3.39 (t, J=7.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.78 ppm
(d, J=8.0 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=0.2 (CH3), 15.9
(CH2), 16.2 (CH2), 18.0 (CH2), 21.8 (CH3), 24.9 (CH2), 27.1 (CH2), 50.3
(CH2), 73.5 (C), 77.7 (C), 78.5 (C), 80.6 (C), 127.9 (CH), 129.7 (CH),
134.5 (C), 144.8 ppm (C), C=N unobserved; IR (neat): n˜ =2982, 2361,
151.0 ppm (C); IR (neat): n˜ =2936, 1722, 1348, 1153, 671 cmꢀ1
.
1726, 1350, 1148 cmꢀ1 HRMS: m/z: calcd for [C21H28N2O2NaSSi]+:
;
Step h: NaCN (0.289 g, 5.901 mmol) was added to a solution of the prod-
uct obtained after step g (0.478 g, 0.984 mmol) in DMF (10 mL). The
mixture was warmed to 808C and stirred for 24 h, diluted with Et2O and
washed with water, brine, dried over MgSO4, filtered and concentrated
under reduced pressure. Purification of the crude material by CC (PE/
EtOAc 9:1) afforded 11e as a yellow oil (0.250 g, 81%). Rf =0.37 (PE/
EtOAc 9:1); 1H NMR (200 MHz, CDCl3): d=1.57–1.63 (m, 4H), 1.71–
1.76 (m, 2H), 2.16–2.19 (m, 4H), 2.37 (t, J=7.0 Hz, 2H), 2.42 (s, 3H),
3.05 (q, J=6.5 Hz, 2H), 4.70 (t, J=6.5 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H),
7.73 ppm (d, J=8.0 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=16.2 (CH2),
16.9 (CH2), 18.0 (CH2), 21.7 (CH3), 24.5 (CH2), 27.7 (CH2), 28.6 (CH2),
42.5 (CH2), 79.7 (C), 80.2 (C), 119.7 (C), 127.2 (CH), 129.8 (CH), 137.0
423.15330; found: 423.15384.
2d: Method A: Compound 1d (30 mg, 0.075 mmol) was added to a solu-
tion of [CpCoACHTUNGTRENNUNG(C2H4)2] (0.72 mg, 0.004 mmol) in THF (2 mL) under Ar in
a Schlenk tube. After 1 h (TLC monitoring), SiO2 was added and the sol-
vent was removed under reduced pressure. CC of the crude material
(PE/EtOAc 4:1) afforded a white solid (30 mg, 100%). Rf =0.40 (PE/
EtOAc 8:2); 1H NMR (400 MHz, CDCl3): d=0.44 (s, 9H), 1.14–1.22 (m,
1H), 1.40–1.50 (m, 1H), 1.68–1.77 (m, 1H), 2.10–2.25 (m, 3H), 2.42 (s,
3H), 2.69 (t, J=7.5 Hz, 2H), 3.06–3.11 (m, 2H), 3.37–3.44 (m, 1H), 4.06–
4.13 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.20 ppm (d, J=8.0 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=0.5 (CH3), 21.5 (CH2), 21.7 (CH2), 22.3
(CH2), 23.1 (CH2), 28.6 (CH3), 34.5 (CH2), 45.4 (CH2), 127.8 (CH), 129.6
(CH), 133.4 (C), 136.7 (C), 136.8 (C), 139.0 (C), 143.7 (C), 163.5 (C),
165.5 ppm (C); IR (neat): n˜ =2954, 2360, 1160, 838 cmꢀ1; HRMS: m/z:
calcd for [C21H29N2O2SSi]+: 401.17135; found: 401.17156.
(C), 143.5 ppm (C); IR (neat): n˜ =3270, 2931, 1323, 1155 cmꢀ1
.
1e: KHMDS (0.5m in toluene, 720 mL, 0.354 mmol) was added under vig-
orous stirring to a solution of 11e (0.100 g, 0.314 mmol) in toluene under
Ar in a Schlenk tube. After 10 min, iodonium salt 7 (0.185 g, 0.411 mmol)
was added and the reaction mixture heated at 808C (bath temperature)
for 24 h. After TLC monitoring, SiO2 was added, the solvent was re-
moved under reduced pressure and CC of the material (PE/EtOAc 8:2)
afforded a yellow oil (45 mg, 30%). Rf =0.27 (PE/EtOAc 8:2); 1H NMR
(200 MHz, CDCl3): d=0.15 (s, 9H), 1.60–1.66 (m, 2H), 1.75–1.80 (m,
4H), 2.10–2.25 (m, 4H), 2.34 (t, J=7.0 Hz, 2H), 2.45 (s, 3H), 3.45 (t, J=
6.5 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.76 ppm (d, J=8.0 Hz, 2H);
13C NMR (50 MHz, CDCl3): d=0.2 (CH3), 15.9 (CH2), 16.9 (CH2), 18.1
(CH2), 21.7 (CH3), 24.6 (CH2), 27.3 (CH2), 27.7 (CH2), 50.3 (CH2), 66.9
(C), 73.7 (C), 79.8 (C), 95.3 (C), 103.9 (C), 127.9 (CH), 129.7 (CH), 134.0
9e: 1H NMR (200 MHz, CDCl3): d=1.19 (t, J=7.0 Hz, 3H), 1.31 (d, J=
5.0 Hz, 3H), 1.54–1.59 (m, 2H), 1.63–1.70 (m, 2H), 1.72 (quint, J=
7.0 Hz, 2H, and OH), 2.16 (tt, J=7.0, 2.5 Hz, 2H), 2.26 (tt, J=7.0,
2.5 Hz, 2H), 3.40–3.48 (m, 2H), 3.53–3.63 (m, 2H), 3.74 (t, J=6.0 Hz,
2H), 4.66 ppm (q, J=5.0 Hz, H); 13C NMR (50 MHz, CDCl3): d=15.4
(CH3), 15.5 (CH2), 18.7 (CH2), 20.0 (CH3), 25.9 (CH2), 29.2 (CH2), 31.7
(CH2), 60.8 (CH2), 62.1 (CH2), 64.8 (CH2), 79.8 (C), 80.8 (C), 99.7 ppm
(CH); IR (neat): n˜ =3380, 2930, 2350 cmꢀ1
.
10e: PPh3 (0.557 g, 2.13 mmol) and TsNHBoc (0.576 g, 2.13 mmol) were
successively added to a solution of 9e (0.485 g, 2.13 mmol) in THF
Chem. Eur. J. 2009, 15, 2129 – 2139
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2135

C. Aubert, M. Malacria et al.
(C), 144.8 ppm (C); IR (neat): n˜ =2955, 2360, 2341, 2160, 1366, 1170,
844 cmꢀ1; HRMS: m/z: calcd for [C22H30N2O2NaSi]+: 437.16895; found:
437.16960.
vent under reduced pressure, a CC of the crude material (PE/EtOAc 9:1)
afforded a yellow oil (70 mg, 19%). Rf =0.97 (PE/EtOAc 4:1); 1H NMR
(400 MHz, CDCl3): d=0.15 (s, 9H), 1.81 (q, J=7.0 Hz, 2H), 2.31 (tt, J=
7.2, 2.3 Hz, 2H), 2.44 (s, 3H), 2.45–2.51 (m, 4H), 3.42 (t, J=7.0 Hz, 2H),
7.33 (d, J=8.0 Hz, 2H), 7.74 ppm (d, J=8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=0.2 (CH3), 16.2 (CH2), 18.0 (CH2), 18.7 (CH2),
21.8 (CH3), 24.7 (CH2), 50.4 (CH2), 73.8 (C), 77.9 (C), 79.9 (C), 94.5 (C),
119.5 (C), 127.9 (CH), 129.8 (CH), 134.5 (C), 144.9 ppm (C); IR (neat):
2e: Method A: Compound 1e (40 mg, 0.096 mmol) was added to a solu-
tion of [CpCoACHTUNGTRENNUNG(C2H4)2] (0.90 mg, 0.005 mmol) in THF (2 mL) under Ar in
a Schlenk tube. After 1 h, SiO2 was added and the solvent removed in
vacuo. CC of the material (PE/EtOAc 4:1) afforded a white solid (40 mg,
100%). Rf =0.30 (PE/EtOAc 8:2); 1H NMR (400 MHz, CDCl3): d=0.41
(s, 9H), 1.04–1.12 (m, 1H), 1.32–1.42 (m, 1H), 1.63–1.70 (m, 1H), 1.77–
1.85 (m, 4H), 2.22–2.29 (m, 1H), 2.39 (s, 3H), 2.42 (m, 2H), 2.89–3.02
(m, 2H), 3.34–3.41 (m, 1H), 4.00–4.07 (m, 1H), 7.15 (d, J=8.0 Hz, 2H),
7.28 ppm (d, J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=0.4 (CH3),
21.5 (CH2), 21.9 (CH2), 22.0 (CH2), 23.1 (CH2), 23.3 (CH3), 25.7 (CH2),
33.7 (CH2), 45.5 (CH2), 128.2 (CH), 129.9 (CH), 136.4 (C), 137.0 (C),
137.1 (C), 141.3 (C), 143.9 (C), 155.5 (C), 164.4 ppm (C); IR (neat): n˜ =
n˜ =2958, 2361, 2158, 1368, 1170, 844 cmꢀ1
2 f: Method A: Compound 1 f (30 mg, 0.078 mmol) was added to a solu-
tion of [CpCo(C2H4)2] (0.70 mg, 0.004 mmol) in THF (2 mL) under Ar in
.
AHCTUNGTRENNUNG
a Schlenk tube. After 1 h (TLC monitoring), SiO2 was added and the sol-
vent was removed under reduced pressure. CC of the crude material
(PE/EtOAc 4:1) afforded a white solid (30 mg, 90%). Rf =0.90 (PE/
1
EtOAc 4:1); m.p. 158.38C; H NMR (400 MHz, CDCl3): d=0.44 (s, 9H),
2937, 2360, 2341, 1397, 1162, 840 cmꢀ1
[C22H31N2O2SSi]+: 415.18700; found: 415.18722.
;
HRMS: m/z: calcd for
1.92 (t, J=7.5 Hz, 2H), 2.09 (q, J=7.5 Hz, 2H), 2.38 (s, 3H), 2.60 (t, J=
7.5 Hz, 2H), 3.02 (t, J=7.5 Hz, 2H), 3.89 (t, J=7.5 Hz, 2H), 7.33 (d, J=
8.0 Hz, 2H), 7.74 ppm (d, J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=0.1 (CH3), 21.7 (CH3), 23.5 (CH2), 26.7 (CH2), 29.1 (CH2), 34.3 (CH2),
51.4 (CH2), 128.0 (CH), 129.5 (CH), 132.1 (C), 134.2 (C), 140.0 (C), 143.8
(C), 144.2 (C), 158.1 (C), 164.2 ppm (C); IR (neat): n˜ =2954, 1382,
1164 cmꢀ1; HRMS: m/z: calcd for [C20H27N2O2SSi]+: 387.15570; found:
387.15529.
9 f: BuLi (2.5m in hexanes, 2.1 mL, 5.1 mmol) was added to toluene-4-sul-
fonic acid pent-4-ynyl ester (1.0 g, 4.2 mmol) in THF (4 mL) at ꢀ788C,
followed after 30 min by ethylene oxide (0.63 mL, 12.6 mmol) and
BF3·OEt2 (0.63 mL, 5.1 mmol). After 2 h at ꢀ788C, the reaction mixture
was quenched with strd aq. NH4Cl, extracted with Et2O, washed with
brine, dried over MgSO4, filtered and concentrated under reduced pres-
sure. Purification by CC (PE/EtOAc 3:2) afforded a colorless oil (0.55 g,
46%). 1H NMR (400 MHz, CDCl3): d=1.81 (quint, J=6.3 Hz, 2H), 1.94
(brs, 1H), 2.24 (tt, J=6.8, 2.2 Hz, 2H), 2.34 (tt, J=6.2, 2.2 Hz, 2H), 2.44
(s, 3H), 3.63 (t, J=6.2 Hz, 2H), 4.14 (t, J=6.0 Hz, 2H), 7.34 (d, J=
8.1 Hz, 2H), 7.78 ppm (d, J=8.1 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d=15.1 (CH2), 21.7 (CH3), 23.2 (CH2), 28.2 (CH2), 61.4 (CH2), 69.1
(CH2), 78.2 (C), 80.0 (C), 128.0 (CH), 129.9 (CH), 133.2 (C), 144.9 ppm
(C); IR (neat): n˜ =3375, 2922, 1353, 1188, 924 cmꢀ1; HRMS: m/z: calcd
for [C14H18O4NaS]+: 305.0824; found: 305.0817.
3g: A mixture of chloroacetonitrile (3.2 mL, 50.0 mmol) and malonic
acid dimethyl ester (6.61 g, 50.0 mmol) in THF (50 mL) was added drop-
wise to a suspension of NaH (60 wt% in oil, 2.01 g, 50.0 mmol) in THF
(50 mL) at 08C. 2 h after warming to room temperature, the mixture was
diluted with Et2O, quenched with strd aq. NH4Cl, extracted with CH2Cl2,
washed with brine, dried over MgSO4, filtered and concentrated under
reduced pressure. The crude was purified by distillation under reduced
pressure (1108C, 8.10ꢀ2 Torr) to afford a colorless oil (3.63 g, 42%).
1H NMR (400 MHz, CDCl3): d=2.92 (d, J=6.9 Hz, 2H), 3.74 (t, J=
7.2 Hz, 1H), 3.81 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=17.1
(CH2), 47.9 (CH), 53.6 (CH3), 116.7 (C), 166.9 ppm (C); IR (neat): n˜ =
2959, 2922, 2196, 1736, 1217 cmꢀ1; HRMS: m/z: calcd for [C7H9NO4Na]+:
194.04238; found: 194.04200.
10 f: PPh3 (1.02 g, 3.90 mmol) and TsNHBoc (1.05 g, 3.90 mmol) were
successively added to
a solution of 9 f (1.10 g, 3.90 mmol) in THF
(20 mL) under Ar at 08C, followed by the dropwise addition over 1 h of
DIAD (0.65 mL, 3.90 mmol) with a syringe pump. After 3 h, SiO2 was
added and the solvent removed under reduced pressure. Purification by
CC (PE/EtOAc 7:3) afforded a pale-yellow oil (1.1 g, 53%). Rf =0.56
(PE/EtOAc 3:2); 1H NMR (200 MHz, CDCl3): d=1.32 (s, 9H), 1.80
(quint, J=6.9 Hz, 2H), 2.11 (tt, J=6.8, 2.3 Hz, 2H), 2.35 (brs, 6H), 2.51
(tt, J=8.0, 2.0 Hz, 2H), 3.88 (t, J=7.4 Hz, 2H), 4.97 (quint, J=6.3 Hz,
2H), 7.29 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.4 Hz,
2H), 7.79 ppm (d, J=8.4 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=15.2
(CH2), 20.3 (CH2), 21.8 (CH3), 22.1 (CH3), 28.0 (CH3), 28.2 (CH2), 45.8
(CH2), 69.2 (CH2), 70.2 (C), 80.2 (C), 84.6 (C), 127.9 (CH), 128.1 (CH),
129.4 (CH), 130.0 (CH), 133.2 (C), 137.5 (C), 144.4 (C), 144.9 (C),
5g: Step a: A mixture of 3g (3.57 g, 20.86 mmol) and toluene-4-sulfonic
acid 6-(tetrahydro-pyran-2-yloxy)-hex-2-ynyl ester (8.0 g, 22.70 mmol) in
THF (30 mL) was added dropwise to a suspension of NaH (60 wt% in
oil, 0.875 g, 21.87 mmol) in THF (30 mL) at 08C. 2 h after warming to
room temperature, the mixture was diluted with Et2O, quenched with
strd aq. NH4Cl, extracted with Et2O, washed with brine, dried over
MgSO4, filtered and concentrated under reduced pressure. The crude was
purified by CC (PE/EtOAc 9:1) to afford a colorless oil (2.91 g, 39%).
1
Rf =0.05 (PE/EtOAc 9:1); H NMR (400 MHz, CDCl3): d=1.51–1.79 (m,
8H), 2.23 (tt, J=7.0, 2.4 Hz, 2H), 2.94 (s, 2H), 3.10 (s, 2H), 3.37–3.51
(m, 2H), 3.72–3.85 (m, 8H), 4.55 ppm (brs, 1H); 13C NMR (100 MHz,
CDCl3): d=15.3 (CH2), 19.4 (CH2), 21.6 (CH2), 23.8 (CH2), 25.3 (CH2),
28.7 (CH2), 30.5 (CH2), 53.4 (CH3), 55.0 (C), 61.9 (CH2), 65.5 (CH2), 72.7
(C), 84.5 (C), 98.6 (CH), 115.9 (C), 167.8 ppm (C); IR (neat): n˜ =2946,
150.9 ppm (C); IR (neat): n˜ =2924, 2361, 1727, 1355, 1174, 1156 cmꢀ1
HRMS: m/z: calcd for [C26H33O7NNaS2]+: 558.1596; found: 558.1597.
;
11 f: NaCN (0.312 g, 4.80 mmol) was added to a solution of 10 f (0.847 g,
2.40 mmol) in DMSO (4 mL). The mixture was warmed to 808C for 12 h,
cooled to room temperature, diluted with Et2O, washed with water,
brine, dried over MgSO4, filtered and concentrated under reduced pres-
sure. Purification of the crude material by CC (PE/EtOAc 3:2) afforded
2249, 1739, 1436, 1203, 1032 cmꢀ1
;
HRMS: m/z: calcd for
[C18H25NO6Na]+: 374.15741; found: 374.15709.
Step b: The product obtained after step a (1.51 g, 4.30 mmol) and
PTSA·H2O (0.030 g, 0.16 mmol) were stirred in MeOH (110 mL) for 5 h.
The reaction mixture was quenched with water, extracted with Et2O,
washed with brine, dried over MgSO4, filtered and concentrated under
reduced pressure to afford 5g as a colorless oil (0.93 g, 81%). Rf =0.08
(PE/Et2O 1:1); 1H NMR (400 MHz, CDCl3): d=1.69 (m, 3H), 2.25 (tt,
J=6.9, 2.4 Hz, 2H), 2.96 (t, J=2.3 Hz, 2H), 3.11 (s, 2H), 3.68 (t, J=
6.1 Hz, 2H), 3.79 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=15.3
(CH2), 22.0 (CH2), 24.1 (CH2), 31.4 (CH2), 53.8 (CH3), 55.3 (C), 61.5
(CH2), 73.3 (C), 84.8 (C), 116.2 (C), 168.1 ppm (C); IR (neat): n˜ =3402,
a
yellow oil (0.310 g, 45%). Rf =0.31 (PE/EtOAc 3:2); 1H NMR
(200 MHz, CDCl3): d=1.80 (q, J=6.0 Hz, 2H), 2.25–2.37 (m, 4H), 2.43
(s, 3H), 2.46 (t, J=6.0 Hz, 2H), 3.05 (q, J=7.0 Hz, 2H), 4.81 (t, J=
6.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.74 ppm (d, J=8.0 Hz, 2H);
13C NMR (50 MHz, CDCl3): d=16.3 (CH2), 18.0 (CH2), 20.2 (CH2), 21.7
(CH3), 24.5 (CH2), 42.1 (CH2), 78.3 (C), 80.0 (C), 119.4 (C), 127.2 (CH),
129.9 (CH), 137.0 (C), 143.7 ppm (C); IR (neat): n˜ =3271, 2923, 1323,
1155 cmꢀ1; HRMS: m/z: calcd for [C15H18N2O2NaS]+: 313.0987; found:
313.0971.
2955, 1736, 1436, 1210, 1057 cmꢀ1
;
HRMS: m/z: calcd for
1 f: Potassium carbonate (0.288 g, 2.088 mmol), 1,10-phenanthroline
(0.038 g, 0.209 mmol), CuSO4·5H2O (0.026 g, 0.104 mmol) and 2-bromoe-
thynyltrimethylsilane (0.203 g, 1.149 mmol) were successively added in a
[C13H17NO5Na]+: 290.09989; found: 290.09958.
6g: Compound 5g (0.905 g, 3.38 mmol) in THF (4 mL) and PPh3
(0.933 g, 3.56 mmol) were successively added to a solution of TsNHBoc
(0.922 g, 3.40 mmol) in THF (30 mL) under Ar at 08C, followed by the
dropwise addition over 3 h of DIAD (0.70 mL, 3.55 mmol) in THF
sealed tube to
a solution of 11 f (0.303 g, 1.044 mmol) in toluene
(1.0 mL). The mixture was then heated for 36 h at 608C (bath tempera-
ture). After filtration over a short pad of Celite and removal of the sol-
2136
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 2129 – 2139

Tricyclic Fused 3-Aminopyridines
FULL PAPER
(6 mL) with a syringe pump. After 2 h, SiO2 was added and the solvent
removed under reduced pressure. Purification by CC (PE/CH2Cl2 2:8 to
CH2Cl2/Et2O 95:5) afforded a colorless oil containing 6g admixed with
TsNHBoc which was removed by washing with 1m aq. NaOH to give a
colorless oil (0.736 g, 42%). Rf =0.41 (CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=1.28 (s, 9H), 1.86 (q, J=7.0 Hz, 2H), 2.19 (t, J=6.8 Hz, 2H),
2.38 (s, 3H), 2.93 (s, 2H), 3.14 (s, 2H), 3.75 (s, 6H), 3.82 (t, J=7.4 Hz,
2H), 7.26 (d, J=8.2 Hz, 2H), 7.73 ppm (d, J=8.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=16.0 (CH2), 21.4 (CH3), 21.7 (CH2), 23.9 (CH2),
27.7 (CH3), 28.9 (CH2), 46.1 (CH2), 53.5 (CH3), 55.1 (C), 73.4 (C), 83.7
(C), 84.1 (C), 116.1 (C), 127.6 (CH), 129.2 (CH), 137.2 (C), 144.1 (C),
150.7 (C), 167.9 ppm (C); IR (neat): n˜ =2958, 1742, 1356, 1288,
1157 cmꢀ1; HRMS: m/z: calcd for [C25H32N2O8NaS]+: 543.17716; found:
543.17646.
(PE/Et2O 1:1) afforded a solid that was washed with hexane to give a
white solid (8.2 mg, 77%). Rf =0.23 (PE/Et2O 1:1); m.p. 208.08C (dec.);
1H NMR (400 MHz, CDCl3): d=1.25 (brs, 1H), 1.82 (brs, 1H), 2.38 (brs,
5H), 2.58 (brs, 1H), 3.29 (brs, 1H), 3.50 (s, 2H), 3.75 (s, 4H), 3.83 (s,
6H), 4.08 (brs, 1H), 6.80 (d, J=7.1 Hz, 2H), 7.06 (d, J=7.1 Hz, 2H),
7.13 (d, J=7.7 Hz, 2H), 7.46 ppm (d, J=7.7 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=21.7 (CH3), 21.8 (CH2), 22.7 (CH2), 36.8 (CH2),
42.1 (CH2), 45.3 (CH2), 53.3/53.4 (CH3), 55.4 (CH3), 58.3 (C), 113.7 (CH),
127.7 (CH), 129.3 (CH), 129.9 (C), 130.3 (CH), 130.7 (C), 132.6 (C),
136.6 (C), 142.6 (C), 143.5 (C), 156.6 (C), 158.5 (C), 159.6 (C), 171.8/
172.0 ppm (C); IR (neat): n˜ =2954, 2360, 1735, 1247 cmꢀ1; HRMS: m/z:
calcd for [C29H31N2O7S]+: 551.18465; found: 551.18312.
3h: NaH (60 wt% in oil, 1.31 g, 33.10 mmol) and bromoacetonitrile
(4.76 g, 39.72 mmol) were added to a solution of 6-(tetrahydro-pyran-2-
yloxy)-hex-2-yn-1-ol (6.56 g, 33.10 mmol) in DMF (160 mL) at 08C. The
mixture was warmed to room temperature. After 30 min, the mixture was
diluted with Et2O, quenched with strd aq. NH4Cl, extracted with Et2O,
washed with brine, dried over MgSO4, filtered and concentrated under
reduced pressure. The crude was purified by CC (PE/Et2O 1:1) to afford
1g: Step d: A solution of 6g (0.695 g, 1.33 mmol) in CH2Cl2 (5 mL) and
freshly distilled TFA (100 mL, 1.35 mmol) was microwaved at 1108C for
2 h. The reaction mixture was quenched with water, extracted with
CH2Cl2, washed with brine, dried over MgSO4, filtered and concentrated
under reduced pressure to afford, after purification by CC (CH2Cl2 to
CH2Cl2/Et2O 95:5), a colorless oil (0.447 g, 80%). Rf =0.20 (CH2Cl2/Et2O
95:5); 1H NMR (400 MHz, CDCl3): d=1.59 (q, J=6.8 Hz, 2H), 2.15 (tt,
J=6.8, 2.2 Hz, 2H), 2.40 (s, 3H), 2.90 (t, J=2.2 Hz, 2H), 2.95 (q, J=
6.7 Hz, 2H), 3.06 (s, 2H), 3.76 (s, 6H), 5.18 (t, J=6.2 Hz, 1H), 7.29 (d,
J=8.3 Hz, 2H), 7.73 ppm (d, J=8.3 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=15.7 (CH2), 21.4 (CH3), 21.8 (CH2), 23.9 (CH2), 28.4 (CH2),
41.9 (CH2), 53.6 (CH3), 55.1 (C), 73.6 (C), 83.8 (C), 116.2 (C), 127.0
(CH), 129.7 (CH), 136.9 (C), 143.4 (C), 168.0 ppm (C); IR (neat): n˜ =
3284, 1737, 1435, 1156 cmꢀ1; HRMS: m/z: calcd for [C20H24N2O6NaS]+:
443.12473; found: 443.12431.
a
colorless oil (1.17 g, 15%). Rf =0.45 (PE/Et2O 1:1); 1H NMR
(400 MHz, CDCl3): d=1.49–1.82 (m, 8H), 2.33 (tt, J=7.1, 2.1 Hz, 2H),
3.40–3.50 (m, 2H), 3.72–3.86 (m, 2H), 4.26 (s, 2H), 4.32 (s, 2H),
4.55 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3): d=15.1 (CH2), 19.1
(CH2), 25.0 (CH2), 28.2 (CH2), 30.2 (CH2), 53.4 (CH2), 58.2 (CH2), 61.6
(CH2), 65.2 (CH2), 73.3 (CH2), 88.5 (CH2), 98.2 (CH), 115.4 ppm (C); IR
(neat): n˜ =2941, 2231, 1323, 1031 cmꢀ1
[C13H19NO3Na]+: 260.12571; found: 260.12550.
; HRMS: m/z: calcd for
5h: Compound 3h (1.14 g, 4.82 mmol) and PTSA·H2O (0.036 g,
0.19 mmol) were stirred in MeOH (90 mL) for 5 h. The reaction mixture
was quenched with water, extracted with Et2O, washed with brine, dried
over MgSO4, filtered and concentrated under reduced pressure to afford
Step e: BuLi (2.4m in hexanes, 370 mL, 0.910 mmol) was added to a solu-
tion of the product obtained after step d (0.376 g, 0.894 mmol) in THF
(15 mL) at ꢀ788C under Ar in a Schlenk tube. After warming to room
temperature the yellow solution was concentrated under reduced pres-
sure to give a solid directly diluted with toluene (15 mL). Iodonium salt 7
(0.460 g, 1.020 mmol) was added in portions over 5 min. After a further
2 h, SiO2 was added and the solvent removed under reduced pressure.
CC of the crude material (PE/Et2O 3:2) afforded a yellow oil (167 mg,
36%). Rf =0.51 (PE/Et2O 3:2); 1H NMR (400 MHz, CDCl3): d=0.11 (s,
9H), 1.74 (q, J=6.8 Hz, 2H), 2.17 (tt, J=6.8, 2.2 Hz, 2H), 2.41 (s, 3H),
2.93 (t, J=2.6 Hz, 2H), 3.11 (s, 2H), 3.32 (t, J=6.8 Hz, 2H), 3.76 (s, 6H),
7.31 (d, J=8.2 Hz, 2H), 7.75 ppm (d, J=8.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=0.0 (CH3), 15.6 (CH2), 21.6 (CH3), 21.8 (CH2),
23.9 (CH2), 26.9 (CH2), 49.9 (CH2), 53.6 (CH3), 55.1 (C), 73.3 (C), 73.7
(C), 83.5 (C), 94.8 (C), 116.1 (C), 127.7 (CH), 129.7 (CH), 134.2 (C),
1
a pale yellow oil (0.533 g, 72%). H NMR (400 MHz, CDCl3): d=1.65 (q,
J=6.8 Hz, 2H), 2.25 (tt, J=7.1, 2.1 Hz, 2H), 2.96 (brs, 1H), 3.58 (t, J=
6.1 Hz, 2H), 4.19 (t, J=2.2 Hz, 2H), 4.26 ppm (s, 2H); 13C NMR
(100 MHz, CDCl3): d=14.9 (CH2), 30.8 (CH2), 53.8 (CH2), 58.7 (CH2),
60.7 (CH2), 73.5 (C), 88.9 (C), 115.7 ppm (C); IR (neat): n˜ =3366, 2927,
2229, 1085 cmꢀ1
;
HRMS: m/z: calcd for [C8H11NO2Na]+: 176.06820;
found: 176.06797.
6h: Compound 5h (0.530 g, 3.46 mmol) in THF (12 mL) and PPh3
(1.00 g, 3.81 mmol) were successively added to a solution of TsNHBoc
(0.988 g, 3.64 mmol) in THF (12 mL) under Ar at 08C, followed by the
dropwise addition over 4 h of DIAD (0.768 g, 3.80 mmol) in THF (6 mL)
with a syringe pump. After 12 h, SiO2 was added and the solvent re-
moved under reduced pressure. Purification by CC (PE/CH2Cl2 2:8 to
144.7 (C), 167.9 ppm (C); IR (neat): n˜ =2956, 2157, 1740, 1168, 841 cmꢀ1
;
HRMS: m/z: calcd for [C25H32N2O6NaSSi]+: 539.16426; found: 539.16333.
CH2Cl2/Et2O 95:5) afforded
a colorless oil (0.46 g, 33%). Rf =0.35
(CH2Cl2); 1H NMR (400 MHz, CDCl3): d=1.34 (s, 9H), 1.99 (q, J=
7.2 Hz, 2H), 2.35 (tt, J=7.0, 2.2 Hz, 2H), 2.43 (s, 3H), 3.92 (t, J=7.3 Hz,
2H), 4.29 (s, 2H), 4.40 (s, 2H), 7.31 (d, J=7.9 Hz, 2H), 7.77 ppm (d, J=
7.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=16.2 (CH2), 21.4 (CH3),
27.7 (CH3), 28.7 (CH2), 46.2 (CH2), 53.8 (CH2), 58.5 (CH2), 74.1 (C), 84.2
(C), 88.2 (C), 115.8 (C), 127.6 (CH), 129.2 (CH), 137.2 (C), 144.2 (C),
150.8 ppm (C); IR (neat): n˜ =2978, 1723, 1349, 1154, 1086 cmꢀ1; HRMS:
m/z: calcd for [C20H26N2O5NaS]+: 429.14546; found: 429.14492.
2g: Method A: Compound 1g (145 mg, 0.280 mmol) in THF (1 mL) was
added to [CpCo
ACHTUNGTRENNUNG
tube. After 12 h (TLC monitoring), some [CpCoACHTUNGTRENNUNG
(4.6 mg, 0.025 mmol). After a further 2 h, SiO2 was added and the solvent
removed under reduced pressure. Two successive CC of the mixture (PE/
Et2O 1:1) afforded a white solid (110 mg, 76%). Rf =0.29 (PE/Et2O 1:1);
m.p. 173.38C; 1H NMR (400 MHz, CDCl3): d=0.42 (s, 9H), 1.17–1.27
(m, 2H), 1.39–1.50 (m, 1H), 1.65–1.75 (m, 1H), 2.15–2.22 (m, 1H), 2.42
(s, 3H), 3.25/3.29 (2s, 1H), 3.37–3.41 (m, 2H), 3.74/3.76 (2s, 1H), 3.78/
3.81 (2s, 6H), 4.05–4.12 (m, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.28 ppm (d,
J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=0.4 (CH3), 21.1 (CH2),
21.7 (CH3), 22.2 (CH2), 36.6 (CH2), 42.0 (CH2), 45.1 (CH2), 53.2 (CH3),
58.1 (C), 127.8 (CH), 129.7 (CH), 129.8 (C), 136.4 (C), 137.4 (C), 139.0
(C), 143.8 (C), 158.7 (C), 167.2 (C), 171.9 ppm (C); IR (neat): n˜ =2953,
1h: Step c: A solution of 6h (0.416 g, 1.02 mmol) in CH2Cl2 (5 mL) and
freshly distilled TFA (76 mL, 1.02 mmol) was microwaved at 1108C for
2 h. The reaction mixture was quenched with water, extracted with
CH2Cl2, washed with brine, dried over MgSO4, filtered and concentrated
under reduced pressure to afford, after purification by CC (CH2Cl2 to
CH2Cl2/Et2O 95:5), a yellow oil (0.24 g, 77%). Rf =0.55 CH2Cl2/Et2O
95:5); 1H NMR (400 MHz, CDCl3): d=1.65 (q, J=6.8 Hz, 2H), 2.44 (tt,
J=6.9, 2.1 Hz, 2H), 2.39 (s, 3H), 2.97 (q, J=6.6 Hz, 2H), 4.20 (t, J=
2.1 Hz, 2H), 4.29 (s, 2H), 5.26 (t, J=6.2 Hz, 1H), 7.27 (d, J=7.9 Hz,
2H), 7.78 ppm (d, J=7.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=15.8
(CH2), 21.4 (CH3), 28.0 (CH2), 41.9 (CH2), 54.0 (CH2), 58.7 (CH2), 74.3
(C), 88.1 (C), 115.9 (C), 127.0 (CH), 129.7 (CH), 136.7 (C), 143.4 ppm;
IR (neat): n˜ =3278, 2925, 1322, 1154, 1086 cmꢀ1; HRMS: m/z: calcd for
[C15H18N2O3NaS]+: 329.09303; found: 329.09276.
1736, 1162, 844 cmꢀ1
;
HRMS: m/z: calcd for [C25H33N2O6SSi]+:
517.18231; found: 517.18160.
13: PPh3 (1.2 mg, 0.0046 mmol) and CuI (8.3 mg, 0.0436 mmol) were suc-
cessively added to a solution of [PdCl2ACHTNUTRGNEUGN(PPh3)2] (1.2 mg, 0.0017 mmol) in
degassed DMF (0.2 mL) under Ar, followed by 4-iodoanisole (4.5 mg,
0.0192 mmol), 2g (20.0 mg, 0.0387 mmol), and TBAF (1m in THF, 80 mL,
0.080 mmol). The orange reaction mixture turned brown after 24 h. Re-
moval of DMF under reduced pressure and CC of the crude material
Chem. Eur. J. 2009, 15, 2129 – 2139
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2137

C. Aubert, M. Malacria et al.
Step d: BuLi (2.4m in hexanes, 150 mL, 0.360 mmol) was added to a solu-
tion of the product obtained after step c (0.117 g, 0.382 mmol) in THF
(6 mL) at ꢀ788C under Ar in a Schlenk tube. After warming to room
temperature, the yellow solution was concentrated under reduced pres-
sure to give a solid directly diluted with toluene (6 mL). Iodonium salt 7
(0.195 g, 0.433 mmol) was added in portions over 5 min. After a further
2 h, SiO2 was added and the solvent removed under reduced pressure.
CC of the crude material (PE/Et2O 4:1) afforded a yellow oil (17 mg,
11%). Rf =0.40 (PE/Et2O 3:2); 1H NMR (400 MHz, CDCl3): d=0.15 (s,
9H), 1.86 (q, J=6.8 Hz, 2H), 2.33 (tt, J=6.9, 2.2 Hz, 2H), 2.45 (s, 3H),
3.40 (t, J=6.8 Hz, 2H), 4.30 (t, J=2.1 Hz, 2H), 4.38 (s, 2H), 7.34 (d, J=
8.3 Hz, 2H), 7.78 ppm (d, J=8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=0.2 (CH3), 15.9 (CH2), 21.8 (CH3), 26.7 (CH2), 50.1 (CH2), 54.0 (CH2),
58.7 (CH2), 73.6 (C), 74.5 (C), 88.1 (C), 94.8 (C), 115.8 (C), 127.9 (CH),
129.8 (CH), 134.3 (C), 144.9 ppm (C); IR (neat): n˜ =3069, 2958, 2160,
[4] For a recent example, see: Y. Zhou, J. A. Porco, J. K. Snyder, Org.
Lett. 2007, 9, 393.
[5] B. Heller, A. Gutnov, C. Fischer, H.-J. Drexler, A. Spannenberg, D.
Redkin, C. Sundermann, B. Sundermann, Chem. Eur. J. 2007, 13,
1117.
[6] For a recent example, see: B. L. Gray, X. Wang, W. C. Brown, L.
Kuai, S. L. Schreiber, Org. Lett. 2008, 10, 2621.
[7] For [2+2+2] cocyclizations between an ynamide and two alkynes
to give benzenamines, see: a) B. Witulski, T. Stengel, Angew. Chem.
1999, 111, 2521; Angew. Chem. Int. Ed. 1999, 38, 2426; b) B. Witul-
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1364, 1169, 844 cmꢀ1
;
HRMS: m/z: calcd for [C20H26N2O3NaSSi]+:
425.13256; found: 425.13220.
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2h: Method A: Compound 1h (40 mg, 0.099 mmol) in THF (0.6 mL) was
added to [CpCo
tube. After 4 h (TLC monitoring), some [CpCo
(1.1 mg, 0.006 mmol). After a further 12 h, some [CpCoAHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
0.015 mmol) was added, and after 3 h, SiO2 was added and the solvent re-
moved under reduced pressure. CC of the mixture (PE/Et2O 1:1) afford-
ed a white solid (25 mg, 62%). Rf =0.62 (PE/Et2O 3:7); m.p. 128.28C;
1H NMR (400 MHz, CDCl3): d=0.43 (s, 9H), 1.20–1.28 (m, 1H), 1.43–
1.50 (m, 1H), 1.69–1.74 (m, 1H), 2.10 (m, 1H), 2.41 (s, 3H), 3.39–3.46
(m, 1H), 4.07–4.15 (m, 1H), 4.91–4.99 (m, 2H), 5.06–5.15 (m, 2H), 7.20
(d, J=8.1 Hz, 2H), 7.32 ppm (d, J=8.1 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=0.4 (CH3), 21.2 (CH2), 21.7 (CH3), 22.5 (CH2), 45.4 (CH2),
71.0 (CH2), 73.5 (CH2), 127.8 (CH), 128.8 (C), 129.8 (CH), 136.6 (C),
137.0 (C), 137.8 (C), 144.0 (C), 158.5 (C), 168.2 ppm (C); IR (neat): n˜ =
2949, 1353, 1161, 843 cmꢀ1; HRMS: m/z: calcd for [C20H27N2O3SSi]+:
403.15062; found: 403.15024.
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Acknowledgement
We thank the IUF, Ministꢃre de la Recherche, and CNRS for financial
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Chem. Eur. J. 2009, 15, 2129 – 2139

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Received: November 5, 2008
Published online: January 13, 2009
Chem. Eur. J. 2009, 15, 2129 – 2139
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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