A straightforward synthesis of 1,3-dichloro-5,8-dihydroisoquinoline by consecutive Stille cross-coupling and metathesis reactions

Article abstract of DOI:10.1016/j.tetlet.2009.06.101

An efficient three-step synthetic route from 2,6-dichloro-4-iodopyridine to 1,3-dichloro-5,8-dihydroisoquinoline is described. A ring-closing-metathesis reaction constitutes the key step in this synthetic sequence. The reactivity of both chloro atoms is d

Full text of DOI:10.1016/j.tetlet.2009.06.101

Tetrahedron Letters 50 (2009) 5040–5043
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A straightforward synthesis of 1,3-dichloro-5,8-dihydroisoquinoline
by consecutive Stille cross-coupling and metathesis reactions
*
Adri van den Hoogenband , Jack A. J. den Hartog, Nancy Faber-Hilhorst, Jos H. M. Lange,
Jan Willem Terpstra
Solvay Pharmaceuticals, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient three-step synthetic route from 2,6-dichloro-4-iodopyridine to 1,3-dichloro-5,8-dihydroiso-
quinoline is described. A ring-closing-metathesis reaction constitutes the key step in this synthetic
sequence. The reactivity of both chloro atoms is demonstrated in a Suzuki arylation reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 17 April 2009
Revised 9 June 2009
Accepted 19 June 2009
Available online 25 June 2009
Organometallic chemistry is of significant importance for the
synthesis of a variety of chemical entities. Applications of lithia-
tion,1 modern Grignard,2 transition metal catalysed cross-cou-
pling3 and metathesis chemistry4 have resulted in the synthesis
of many new drug-like compounds which are often hard to prepare
by classical chemistry methods. In addition, organometallic chem-
istry applications in large-scale production have gained more
importance.5 In the course of our research endeavours, we became
interested in the synthesis of 1,3-dichloro-5,8-dihydroisoquinoline
(1) as a novel starting material for Suzuki cross-coupling. Although
there were some initial doubts about the stability of compound 1
and its Suzuki derivatives (potential oxidation by air to the corre-
sponding heteroaromatic 1,3-dichloroisoquinoline), it was decided
to devise a synthetic route towards 1. We envisaged that this might
be possible by application of mild reaction conditions utilising
organometallic chemistry, an area in which we have been active.6
Consequently, efforts were undertaken towards the synthesis of
the novel key intermediate, 2,6-dichloro-3,4-diallylpyridine 2. Ini-
tially, a strategy was selected based on a regioselective direct Grig-
nard reaction developed by Knochel and co-workers,7 followed by
a lithiation reaction (Scheme 1). Disappointingly, treatment of 2,6-
dichloropyridine with in situ prepared 2,2,6,6-tetramethylpiperi-
dine-MgClÁLiCl, followed by transmetallation with CuCNÁ2LiCl
and addition of allyl bromide resulted in a low yield of 2,6-di-
chloro-4-allylpyridine (3). This result prompted the use of com-
mercially available 2,6-dichloro-4-iodopyridine as starting
material for the synthesis of 2. After a sequence involving Grignard
exchange with iPrMgClÁLiCl, transmetallation with CuCNÁ2LiCl and
again trapping the obtained reaction mixture with allyl bromide,
the desired 2,6-dichloro-4-allyl-pyridine (3)8 was isolated in a sat-
isfactory yield of 75% (Scheme 1). It should be mentioned that run-
ning the reaction with n-BuLi at À78 °C instead of iPrMgClÁLiCl at
À10 °C led to a complex reaction mixture. The subsequent step
was the selective introduction of the second allyl group on 3. Thus,
from our experience,9 direct lithiation with LiTMP, in situ trans-
metallation with CuCNÁ2LiCl and addition of allyl bromide were
studied. Surprisingly, compound 410 was isolated in a moderate
yield of 40%, instead of the desired diallylpyridine 2 (Scheme 1).
Apparently, the allyl-CH2 group is easily deprotonated under these
reaction conditions. Therefore, it was decided to switch attention
a)
Cl
N
Cl
Cl
N
Cl
3
c)
c)
Cl
N
Cl
I
2
b)
3
Cl
N
Cl
Cl
N
Cl
4
Scheme 1. Reagents and conditions: (a) (i) 1 mol equiv 2,6-dichloropyridine,
1.2 mol equiv TMPMgClÁLiCl, THF, 0–15 °C, 5 h; (ii) 1.2 mol equiv CuCNÁ2LiCl,
À60 °C to 0 °C, 1 h; (iii) 1.2 mol equiv allyl bromide, À60 °C to rt, 16 h,15%; (b) (i)
1 mol equiv 2,6-dichloro-4-iodopyridine, 1.25 mol equiv i-PrMgCl.LiCl, THF, À50 °C,
30 min; (ii) 1.25 mol equiv CuCNÁ2LiCl, À60 °C to 0 °C, 1 h; (iii) 1.25 mol equiv allyl
bromide, À60 °C to rt, 16 h, 75%; (c) (i) 1 mol equiv 3, 3.2 mol equiv LiTMP, THF,
À70 °C, 3 h; (ii) 3.2 mol equiv CuCNÁ2LiCl, À70 °C to 0 °C, 1 h; (iii)1.3 mol equiv allyl
bromide, À70 °C to rt, 16 h, 40% 4.
* Corresponding author. Tel.: +31 0 294 479605; fax: +31 0 294 477138.
E-mail address: adri.vandenhoogenband@solvay.com (A. van den Hoogenband).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.101

A. van den Hoogenband et al. / Tetrahedron Letters 50 (2009) 5040–5043
5041
to a direct lithiation/cross-coupling strategy for the preparation of
2, as outlined in Scheme 2. After a brief survey of the reaction con-
ditions, novel 2,6-dichloro-3,4-diiodopyridine (5) was prepared in
a reasonable yield of 70% via lithiation at the 3-position of 2,6-di-
chloro-4-iodopyridine with LiTMP at low temperature, followed by
treatment with a solution of iodine in THF.11
this particular reaction (1–9 mmol) had no negative impact on
the observed yield.
The ring-closing metathesis reaction (RCM) was evaluated as
the next step. The application of RCM for the synthesis of azamac-
rocycles, heterocycles, natural compounds and cyclic peptides has
been extensively documented in the literature,17 and we have also
gained some experience in this area.18 Intriguingly, the synthesis of
carbocycles by ring-closing metathesis is relatively less explored in
comparison with heterocycles. Our first attempt to react com-
pound 2 in the presence of 5 mol % Grubbs’ 2nd generation cata-
lyst19 (Fig. 1) over 2.5 h at room temperature in dichloromethane
resulted in an inseparable mixture of the regioisomeric 5,8-, 7,8-
and 5,6-dihydro-1,3-dichloroisoquinolines in a combined yield of
76% and a molar ratio of 2:3:4 (Scheme 3). This observation can
be rationalised by invoking the initial formation of 1, followed by
partial isomerisation of the double bond due to some degradation
of the catalyst to Ru–H. The Ru–H is able to attack the double bond
via a non-selective hydrometallation, followed by a non-selective
ruthenium hydride elimination reaction.20
A number of precedents have been reported to overcome isom-
erisation in RCM. Fustero described the use of Grubbs’ 1st genera-
tion catalyst (Fig. 1)21 and Stevens20 has reported the application of
a catalytic amount of RuClH(CO)(PPh3)3 as an additive to Grubbs’
2nd generation catalyst. Another way to tackle this isomerisation
reaction is described by Grubbs and co-workers. They tested a
number of additives in the presence of Grubbs’ 2nd generation cat-
alyst and found that the addition of a catalytic amount of 1,4-
benzoquinone was very effective in preventing isomerisation.22
These conditions resulted in a clean conversion into compound 1
within 45 min with an isolated yield of 75%23 (Scheme 3). Neither
isomerisation nor oxidation into the corresponding isoquinoline
was observed, which is in contrast with the related synthetic route
to functionalised 5,8-dihydronaphthalenes as reported by Kotha.12
It is interesting to note that our initial concerns about the potential
lack of stability of 1 were unfounded, because after storage of com-
pound 1 for three months under air in a refrigerator at 5 °C, no
trace of degradation was observed by NMR analysis.
With compound 5 in hand, cross-coupling reactions were inves-
tigated to prepare 2,6-dichloro-3,4-diallylpyridine (2). The results
are summarised in Table 1. The first approach was based on the
published work of Kotha et al.12 who converted aryl halides into
the corresponding allyl compounds by a Pd(PPh3)4-mediated Suzu-
ki cross-coupling reaction with allyl boronic pinacol ester and CsF
in refluxing THF. Interestingly, this method was also suitable for
the conversion of 1,2-diodo arenes into the corresponding 1,2-dial-
lyl compounds, which subsequently were applied in ring-closing
metathesis reactions resulting in unstable 1,4-dihydronaphtha-
lenes. Unfortunately, in our hands this Suzuki reaction failed using
5 as starting material (Table 1, entry 1). This prompted the applica-
tion of Stille cross-coupling methodology. Reaction of 5 with trib-
utylallylstannane and Pd(PPh3)4 in DMF at 110 °C13 resulted in the
formation of 2 in a moderate yield, with some concomitant forma-
tion of triallyl chloropyridine (Table 1, entry 2). Lowering the tem-
perature to 85 °C and switching from DMF to dioxane as the
solvent resulted in the mono-allyl compound 6 (Table 1, entry
3).14 Fortunately, repeating this reaction at an elevated tempera-
ture (110 °C) led to the desired compound 2 in a yield of 48% (Table
1, entry 4). Finally, by running the reaction under modified Fu con-
ditions [Pd(PPh3)4, CsF, dioxane, 110 °C],15 compound 2 was iso-
lated in a satisfactory yield of 70% (Table 1, entry 5).16 Scaling up
I
I
I
b)
a)
Cl
N
Cl
Cl
N
Cl
Cl
N
Cl
In order to test 1 as the starting material for Suzuki cross-cou-
pling chemistry, the replacement of both chloro atoms with phenyl
groups was explored. A brief survey of the reaction conditions led
to conversion into 1,3-diphenyl-5,8-dihydroisoquinoline (7) by
treatment of 1 with 3 mol equiv of PhB(OH)2, 9 mol equiv of
K3PO4ÁH2O, 3 mol % of Pd(OAc)2 and 6 mol % of S-Phos (Fig. 1) in de-
gassed toluene at 90 °C for 30 min. Compound 7 was obtained as a
colourless oil in high yield (85%)24 (Scheme 4). In contrast with the
observed stability of compound 1, small impurities were visible in
the NMR spectrum of 7 after a three-month storage period under
air in a refrigerator at 5 °C.
5
2
Scheme 2. Reagents and conditions: (a) (i) 1 mol equiv 2,6-dichloro-4-iodopyri-
dine,1.2 mol equiv LiTMP, THF, À78 °C, 2 h; (ii) 1.2 mol equiv iodine, À78 °C, 70%;
(b) see conditions described in Table 1.
Table 1
I
I
I
or
In conclusion, starting from commercially available 2,6-di-
chloro-4-iodopyridine, a straightforward three-step reaction pro-
cedure has been devised for the preparation of novel 1,3-
dichloro-5,8-dihydroisoquinoline (1). The key step is the RCM of
Cl
N
5
Cl
Cl
N
Cl
Cl
N
Cl
6
2
1 mol equiv
Entry Reaction conditions
Product Yielda
(%)
Mes
N
N
Mes
1
2
3
4
5
2.2 mol equiv H2C@CHCH2Bpin, 2.2 mol equiv CsF,
10 mol % Pd(PPh3)4, THF, 18 h reflux
2.2 mol equiv H2C@CHCH2Sn(Bu)3, 10 mol % Pd(PPh3)4,
DMF, 110 °C, 2 h
2 mol equiv H2C@CHCH2Sn(Bu)3, 5 mol % Pd(PPh3)4,
dioxane, 85 °C, 2 h
2 mol equiv H2C@CHCH2Sn(Bu)3, 5 mol % Pd(PPh3)4,
dioxane, 110 °C, 2 h
2.1 mol equiv H2C@CHCH2Sn(Bu)3, 4.2 mol equiv CsF,
8 mol % Pd(PPh3)4, dioxane, 110 °C, 3 h
5
P(Cy)3
Ru
P(Cy)2
OMe
Cl
Cl
Cl
Cl
Ph
H
2
6
2
2
30b
22
48
70
Ph
H
Ru
MeO
P(Cy)3
P(Cy)3
Grubbs'
Grubbs'
S-Phos
1st generation
catalyst
2nd generation
catalyst
a
Isolated yield of pure compound.
Contaminated with a trace of triallyl chloropyridine.
b
Figure 1.

5042
A. van den Hoogenband et al. / Tetrahedron Letters 50 (2009) 5040–5043
a)
+
+
Cl
N
Cl
Cl
N
Cl
Cl
N
Cl
Cl
N
Cl
7,8-dihydro isomer
5,6-dihydro isomer
2
1
Scheme 3. Reagents and conditions: (a) 1 mol equiv 2, 5 mol % Grubbs’ 2nd generation catalyst, 20 mol % 1,4-benzoquinone, dichloromethane, 25 °C, 75%: compound 1 is
formed as the sole product. In the absence of 1,4-benzoquinone all three isomers are formed (ratio = 2:3:4). See the detailed description in the text.
70–77; (f) Brown, D. H.; Bourassa, D. E.; Brandt, T.; Castaldi, M. J.; Frost, H. N.;
Hawkins, J.; Johnson, P. J.; Massett, S. S.; Neumann, K.; Phillips, J.; Raggon, J. W.;
Rose, P. R.; Rutherford, J. L.; Sitter, B.; Stewart, A. M.; Vetelino, M. G.; Wei, L. Org.
a)
Process Res. Dev. 2005, 9, 440–450; (g) De Vries, J. G. Can. J. Chem. 2001, 79,
B(OH)2
+
1086–1092.
N
Cl
N
Cl
6. (a) van den Hoogenband, A.; Lange, J. H. M.; Terpstra, J. W.; Koch, M.; Visser, G.
M.; Visser, M.; Korstanje, T. J.; Jastrzebski, J. T. B. H. Tetrahedron Lett. 2008, 49,
4122–4124; (b) Van den Hoogenband, A.; Lange, J. H. M.; Den Hartog, J. A. J.;
Henzen, R.; Terpstra, J. W. Tetrahedron Lett. 2007, 48, 4461–4465; (c) Van den
Hoogenband, A.; Lange, J. H. M.; Iwema-Bakker, W. I.; Den Hartog, J. A. J.; Van
Schaik, J.; Feenstra, R. W.; Terpstra, J. W. Tetrahedron Lett. 2006, 47, 4361–4364;
(d) Kuil, M.; Bekedam, E. K.; Visser, G. M.; Van den Hoogenband, A.; Terpstra, J.
W.; Kamer, P. C. J.; Van Leeuwen, P. W. N. M.; Strijdonck, G. P. F. Tetrahedron
Lett. 2005, 46, 2405–2409; (e) Berkheij, M.; Van der Sluis, L.; Sewing, C.; Den
Boer, D. J.; Terpstra, J. W.; Hiemstra, H.; Iwema-Bakker, W. I.; Van den
Hoogenband, A.; Van Maarseveen, J. H. Tetrahedron Lett. 2005, 46, 2369–2371;
Van den (f) Hoogenband, A.; Den Hartog, J. A. J.; Lange, J. H. M.; Terpstra, J. W.
Tetrahedron Lett. 2004, 45, 8535–8537; (g) Van Berkel, S. S.; Van den
Hoogenband, A.; Terpstra, J. W.; Tromp, M.; Van Leeuwen, P. W. N. M.;
Strijdonck, G. P. F. Tetrahedron Lett. 2004, 45, 7659–7662; (h) Lange, J. H. M.;
Hofmeyer, L. J. F.; Hout, F. A. S.; Osnabrug, S. J. M.; Verveer, P. C.; Kruse, C. G.;
Feenstra, R. W. Tetrahedron Lett. 2002, 43, 1101–1104.
7
1
Scheme 4. Reagents and conditions: (a) 1 mol equiv 1, 3 mol equiv PhB(OH)2,
9 mol equiv K3PO4ÁH2O, 3 mol % Pd(OAc)2, 6 mol % S-Phos, toluene, 90 °C, 30 min,
85%.
diallylpyridine 2 into 1 under mild conditions. The two novel inter-
mediates 2 and 5 which are disclosed herein may serve as versatile
synthetic building blocks. Both chlorine atoms in 1 are able to un-
dergo a Suzuki arylation reaction. Additional functionalisation
reactions of 1 are in progress. As a note of interest, besides the
key compounds 1, 2 and 5, compounds 3, 4, 6 and 7 are, to the best
of our knowledge, not described in the literature.
7. (a) Kienle, M.; Dubbaka, S. R.; Del Amo, V.; Knochel, P. Synthesis 2007, 1272–
1278; (b) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 2958–2961.
8. (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333–3336; (b)
Selected analytical data for compound 3:1H NMR (400 MHz, CDCl3): d 3.37 (d,
J = 6 Hz, 2H), 5.14–5.25 (m, 2H), 5.82–5.93 (m, 1H), 7.10 (s, 2H).
Acknowledgements
9. van den Hoogenband, A., unpublished results.
10. Selected analytical data for compound 4: 1H NMR (400 MHz, CDCl3): d 2.40–2.54
(m, 2H), 3.31–3.38 (m, 1H), 5.10–5.21 (m, 4H), 5.60–5.71 (m, 1H), 5.81–5.92
(m, 1H), 7.10 (s, 2H).
We thank Hugo Morren and Arnold den Hartog for the analyti-
cal support, Marjolein Bosch and Jan Peter de Moes for literature
searching support and Hicham Zilaout for helpful suggestions.
11. Typical procedure for the preparation of compound 5: An oven-dried 250-ml,
three-necked reaction vessel was charged with anhydrous THF (50 ml) and
2,2,6,6-tetramethylpiperidine (1.7 g, 12 mmol) under a nitrogen atmosphere.
The resulting magnetically stirred solution was cooled to À78 °C followed by
dropwise addition of n-BuLi (4.8 ml, 2.5 M in n-hexane, 12 mmol). The
temperature was allowed to rise to 0 °C and the reaction mixture was stirred
References and notes
1. For selected literature references describing lithiation, see: (a) Slocum, D. W.;
Shelton, P.; Moran, K. M. Synthesis 2005, 3477–3498; (b) Whisler, M. C.;
MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206–2225;
(c) Beak, P.; Basu, B.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem.
Res. 1996, 29, 552–560; (d) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109–
1117; (e) Snieckus, V. Chem. Rev. 1990, 90, 879–933.
2. For selected reviews, see: (a) Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem.
Commun. 2006, 583–593; (b) Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed.
2003, 42, 4302–4320.
for 30 min. After cooling again to À78 °C,
a solution of 2,6-dichloro-4-
iodopyridine (2.74 g, 10 mmol) in anhydrous THF (15 ml) was added dropwise
and the reaction mixture was stirred for 1.5 h at À78 °C, followed by dropwise
addition of iodine (3.05 g, 10 mmol) in anhydrous THF (15 ml). The resulting
mixture was reacted for 1 h at À78 °C. Subsequently, the reaction was
quenched with a saturated aqueous solution of NH4Cl and diethyl ether was
added. The organic layer was successively separated, extracted with aqueous
NaHSO3, dried over Na2SO4, filtered and concentrated in vacuo. The obtained
crude
5 was dissolved in a minimum of CH2Cl2 and purified by flash
chromatography [silica gel 60 (0.040–0.063 mm, Merck)] with CH2Cl2–
petroleum ether, 1:1 (v/v), to give 2.8 g of pure 5 (70%). 1H NMR (400 MHz,
CDCl3): d 7.76 (s, 1H). 13C NMR (100 MHz, CDCl3): d 108.30, 123.67, 132.72,
150.04, 153.60. HRMS (ES+): calcd for C5H2NCl2I2 (M+H)+ 399.7654; found:
399.7658.
3. (a) De Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions;
Wiley-VCH: New York, 2004; (b) Jang, L.; Buchwald, S. L. Palladium-catalyzed
Aromatic Carbon–Nitrogen Bond formation in Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004; (c) Hartwig, J. F. Palladium-
Catalyzed Amination of Aryl Halides and Related Reactions; John Wiley & Sons:
New York, 2002.
12. Kotha, S.; Shah, V. R.; Mandal, K. Adv. Synth. Catal. 2007, 349, 1159–1172.
13. (a) Markey, M. D.; Kelly, T. R. J. Org. Chem. 2008, 73, 7441–7443; (b) Chang, C.;
Liu, H.; Chow, T. J. J. Org. Chem. 2006, 71, 6302–6304.
4. For selected reviews, see: (a) Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A.
Chem. Eur. J. 2008, 14, 5716–5726; (b) Boeda, F.; Clavier, H.; Nolan, S. P. Chem.
Commun. 2008, 2726–2740; (c) Chattopadhyay, S. K.; Karmaker, S.; Biswas, T.;
Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919–3952; (d)
Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem., Int. Ed. 2006, 45, 2664–
2670; (e) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760–3765; (f) Grubbs,
R. H. Tetrahedron 2004, 60, 7117–7140; (g) Felpin, F. X.; Lebreton, J. Eur. J. Org.
Chem. 2003, 3693–3712; (h) Arjona, O.; Csaky, A. G.; Plumet, J. Eur. J. Org. Chem.
2003, 611–622; (i) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
5. (a) Flahive, E. J.; Ewanicki, B. L.; Sach, N. W.; O’Neill-Slawecki, S. A.; Stankovic,
N. S.; Yu, S.; Guinness, S. M.; Dunn, J. Org. Process Res. Dev. 2008, 12, 637–645;
(b) Zegar, S.; Tokar, C.; Enache, L. A.; Rajagopol, V.; Zeller, W.; O’Connell, M.;
Singh, J.; Muellner, F. W.; Zembower, D. E. Org. Process Res. Dev. 2007, 11, 747–
753; (c) Itoh, T.; Kato, S.; Nonoyama, N.; Wada, T.; Maeda, K.; Mase, T.; Zhao, M.
M.; Song, J. Z.; Tschaen, D. M.; McNamara, J. M. Org. Process Res. Dev. 2006, 10,
822–828; (d) Kerdesky, F. A. J.; Leanna, M. R.; Zhang, J.; Li, W.; Lallaman, J. E.; Ji,
J.; Morton, H. E. Org. Process Res. Dev. 2006, 10, 512–517; (e) Denni-Dischert, D.;
Marterer, W.; Yusuff, N.; Batt, D.; Ramsey, T.; Geng, P.; Michael, W.; Wang, R.
B.; Taplin, F.; Versace, R.; Cesarz, D.; Perez, L. B. Org. Process Res. Dev. 2006, 10,
14. Selected analytical data for compound 6: 1H NMR (400 MHz, CDCl3): d 3.45 (d,
J = 6 Hz, 2H), 5.09–5.16 (m, 1H), 5.19–5.25 (m, 1H), 5.78–5.86 (m, 1H), 7.01 (s,
1H).
15. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38, 2411–2413.
16. Typical procedure for the preparation of compound 2: An oven-dried 250-ml
three-necked reaction vessel was charged with degassed dioxane (100 ml),
followed by addition of
5 (2 g, 5 mmol), tributylallylstannane (3.48 g,
10.5 mmol), CsF (3.19 g, 21 mmol) and Pd(PPh3)4 (0.46 g, 0.4 mmol). The
mixture was magnetically stirred under a nitrogen atmosphere in a pre-heated
oil bath at 110 °C. After 3 h, compound 5 was fully converted into compound 2
(LC–MS monitoring). After cooling to room temperature, the reaction mixture
was diluted with diethyl ether, filtered and concentrated in vacuo. The
obtained crude 2 was further purified by flash chromatography [silica gel 60
(0.040–0.063 mm, Merck)] with CH2Cl2–petroleum ether, 1:3 (v/v), to give
0.78 g of 2 (70%). 1H NMR (400 MHz, CDCl3): d 3.40 (br d, J = 6 Hz, 2H), 3.53 (br
d, J = 6 Hz, 2H), 4.93 (br d, J = 18 Hz, 1H), 5.06–5.12 (m, 2H), 5.21 (dd, J = 11 Hz
and 2 Hz, 1H), 5.81–5.94 (m, 2H), 7.11 (s, 1H). 13C NMR (100 MHz, CDCl3): d

A. van den Hoogenband et al. / Tetrahedron Letters 50 (2009) 5040–5043
5043
32.91, 36.75, 116.64, 118.53, 123.78, 130.97, 133.04, 133.59, 147.93, 150.99,
153.45. HRMS ES+: calcd for C11H12NCl2 (M+H)+ 228.0347; found: 228.0340.
17. Some selected literature references on azamacrocycles/heterocycles: Arisawa,
M. Chem. Pharm. Bull. 2007, 55, 1099–1118; natural compounds: Gradillas, A.;
Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086–6101; cyclic peptides:
Brik, A. Adv. Synth. Catal. 2008, 350, 1661–1675.
by flash chromatography [silica gel (0.040–0.063 mm, Merck)] with CH2Cl2–
petroleum ether, 1:2 (v/v), to give 430 mg of 1 (75%). 1H NMR (400 MHz, CDCl3):
d 3.29–3.35 (m, 2H), 3.37–3.43 (m, 2H), 5.79–5.86 (m, 1H), 5.89–5.96 (m, 1H),
7.04 (s, 1H). 13C NMR (100 MHz, CDCl3): d 27.04, 29.47, 122.25, 122.58, 124.00,
128.07, 147.09, 149.09, 150.14. HRMS (ES+): calcd for C9H8NCl2 (M+H)+
200.0034; found: 200.0038.
18. Van Maarseveen, J. H.; Den Hartog, J. A. J.; Engelen, V.; Finner, E.; Visser, G. M.;
Kruse, C. G. Tetrahedron Lett. 1996, 8249–8252.
19. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.
20. Dieltiens, N.; Stevens, C. V.; Masschelein, K.; Hennebel, G.; Van der Jeught, S.
Tetrahedron 2008, 64, 4295–4303.
24. Typical procedure for the preparation of compound 7: An oven-dried 100-ml
three-necked reaction vessel was charged with degassed toluene (10 ml)
followed by addition of 1 (100 mg, 0.5 mmol), phenylboronic acid (183 mg,
1.5 mmol), K3PO4ÁH2O (1.03 g, 4.5 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol) and
S-Phos (12.4 mg, 0.03 mmol). After magnetic stirring for 30 min under
a
21. Fustero, S.; Sanchez-Rosello, M.; Jimenez, D.; Santz-Cervera, J. F.; Del Pozo, C.;
Acena, J. L. J. Org. Chem. 2006, 71, 2706–2714.
22. Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127,
17160–17161.
23. Typical procedure for the preparation of compound 1: An oven-dried 250-ml three-
necked reaction vessel was charged with anhydrous degassed CH2Cl2 (50 ml),
followed by addition of 2 (650 mg, 2.85 mmol), Grubbs’ 2nd generation catalyst
(120 mg, 0.14 mmol) and 1,4-benzoquinone (60 mg, 0.55 mmol). After magnetic
stirring under a nitrogen atmosphere for 45 min at room temperature [LC–MS,
HPLC, TLC (CH2Cl2–petroleum ether, 1:2) monitoring] the black-coloured
reaction mixture was filtered and concentrated in vacuo. Pure 1 was obtained
nitrogen atmosphere in a pre-heated oil bath at 90 °C [LC–MS, TLC (CH2Cl2)
monitoring], the reaction was complete. The reaction mixture was allowed to
attain room temperature and diluted with diethyl ether, filtered and washed
with water. The organic layer was dried over Na2SO4, filtered and concentrated
in vacuo. Flash chromatography [silica gel (0.040–0.063 mm, Merck)] with
CH2Cl2 delivered 110 mg of 7 (85%). 1H NMR (400 MHz, CDCl3): d 3.29–3.35 (m,
2H), 3.46–3.51 (m, 2H), 5.87–5.95 (m, 2H), 7.34–7.49 (m, 7H), 7.54–7.58 (m,
2H), 8.01–8.07 (m, 2H). 13C NMR (100 MHz, CDCl3): d 28.00, 30.25, 118.97,
123.46, 125.55, 126.76, 126.88, 127.86, 128.09, 128.48, 128.57, 129.13, 139.53,
140.87, 144.87, 154.08, 158.17. HRMS (ES+): calcd for C21H18
284.1439; found: 284.1426.
N
(M+H)+