Pd-catalyzed arylation/ring-closing metathesis approach to azabicycles

Article abstract of DOI:10.1016/j.tetlet.2007.02.070

Palladium-catalyzed arylation followed by Grignard addition to imines and ring-closing metathesis, using Grubbs' catalysts, provides a route to six-, seven-, and eight-membered azabicycles.

Full text of DOI:10.1016/j.tetlet.2007.02.070

Tetrahedron Letters 48 (2007) 2919–2922
Pd-catalyzed arylation/ring-closing metathesis
approach to azabicycles
*
´
´
Unai Martınez-Estıbalez, Nuria Sotomayor and Esther Lete
Departamento de Quı´mica Orga´nica II, Facultad de Ciencia y Tecnologı´a, Universidad del Paı´s Vasco/Euskal
Herriko Unibertsitatea, Apdo. 644, 48080 Bilbao, Spain
Received 30 January 2007; revised 12 February 2007; accepted 14 February 2007
Available online 17 February 2007
Dedicated to Professor Miguel Yus on occasion of his 60th birthday
Abstract—Palladium-catalyzed arylation followed by Grignard addition to imines and ring-closing metathesis, using Grubbs’
catalysts, provides a route to six-, seven-, and eight-membered azabicycles.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Olefin ring-closing metathesis (RCM) has become a
powerful tool in organic synthesis over the past decade,
especially when well-characterized Mo or Ru catalysts
are employed. RCM is now routinely applied to con-
struct cyclic olefins of virtually all ring sizes containing
ether, ester, amide, amine, and other functionalities.1
Additionally, an assortment of Mo- and W-based cata-
lysts is now available to promote asymmetric RCM,
allowing access to non-racemic carbocycles and hetero-
cycles.2 Therefore, it has become clear that strategies
based on RCM can play a crucial role in natural product
synthesis.3 Research in our group during the past years
has involved the development of methods of synthesis of
nitrogen heterocycles.4 Within this context, we herein
describe the combination of Pd-catalyzed arylation
and Grignard reagent addition to imines with ring-
closing metathesis as a strategy for the construction of
six-, seven-, and eight-membered azabicycles.5
First, we examined the Heck reaction of 2-iodoaniline
and allyltrimethylsilane. After extensive experimenta-
tion with different catalytic systems we found that the
reaction resulted in rearrangement to propen-1-yl deriv-
ative 3b. Thus, the use of Pd(dba)3/PPh3/n-Bu4NOAc in
DMF at 50 ꢁC for 24 h led to o-[(E)-2-propen-1-yl]ani-
line 3b (56% yield). All attempts to avoid isomerization
using lower temperatures, shorter reaction times or
other catalytic systems (for instance, Pd(AcO)2/NEt3/
LiCl in DMF) failed.
Scheme 1. Pd-catalyzed arylation. Preparation of anilines 3–4.
This strategy6 requires first the preparation of o-alkenyl
substituted anilines 3 and 4. Table 1 summarizes the
results for the Pd-catalyzed coupling reactions of
2-iodoaniline or the corresponding carbamate with allyl
or vinyltrimethylsilane, or the corresponding stannane
or boroxane compounds.
Therefore, we decided to apply Stille coupling on the cor-
responding carbamate as described in Table 1 (entry 5).
Treatment of carbamate 2 and allyltributylstannane with
Pd(dba)2 and PPh3 in toluene under reflux provided the
2-allylaniline derivative 4a in 66% yield. Although in this
case, no isomerization of the alkene was observed under
these Pd-catalyzed arylation reaction conditions, after
hydrolysis (KOH, EtOH, reflux) of the carbamate, 2-
(propen-1-yl)aniline 3b was isolated in 76% yield. How-
ever, when Pd(PPh3)4 was used as catalyst in DMF at
100 ꢁC, 2-allylaniline 3a could be isolated, after washing
the reaction mixture with NaF solution, in a 47% overall
yield (43% from o-iodoaniline) (entry 6).7
Keywords: Pd-catalyzed arylation; Ring-closing metathesis; Imine
addition; Heterocycles.
*
Corresponding author. Tel.: +34 94602576; fax: +34 946012748;
e-mail: esther.lete@ehu.es
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.070

2920
U. Martı´nez-Estı´balez et al. / Tetrahedron Letters 48 (2007) 2919–2922
Table 1. Pd-catalyzed arylation
Entry
Substrate
Reagents and conditions
R1
Product
3b
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
2
2
2
2
2
AllylTMS/Pd(dba)2, PPh3, n-Bu4NOAc, sieve 4 A, DMF, 50 ꢁC, 24 h
AllylSnBu3/Pd(dba)2, PPh3, toluene, reflux, 24 h
56
32
80
55
66
47b
60
64b
77
3aa
3c
VinylSnBu3/Pd(dba)2, PPh3, toluene, reflux, 20 h
Trivinylcyclotriboroxane/Pd(PPh3)4, K2CO3, DME–H2O, reflux, 20 h
AllylSnBu3/Pd(dba)2, PPh3, toluene, reflux, 24 h
3c
4a
AllylSnBu3/Pd(PPh3)4, DMF, 100 ꢁC, 18 h
3a
VinylSnBu3/Pd(dba)2, PPh3, toluene, reflux, 20 h
4c
VinylSnBu3/Pd(PPh3)4, DMF, 100 ꢁC, 18 h
3c
Trivinylcyclotriboroxane/Pd(PPh3)4, K2CO3, DME–H2O, reflux, 20 h
4c
Preparation of anilines 3–4.
a Compound 3b was also isolated (26%).
b The carbamate was hydrolyzed during work-up by washing the crude, which was washed with NaF.
In view of the moderated yields obtained, we decided to
compare the procedure with the aza-Claisen rearrange-
ment, which has been used by other authors to prepare
2-allylaniline 3a. In our hands, treatment of N-allyl-
aniline (prepared by alkylation of the aniline with allyl
iodide) with BF3ÆEtO2, according to the procedure
described in the literature,8 afforded the 2-allylaniline
in 45% overall yield. Therefore, the Stille coupling
(Table 1, entry 6) is comparable with the aza-Claisen
rearrangement for the synthesis of o-allylaniline 3a,9
while the Heck reaction is the best method for the prep-
aration of o-(2-propenyl)aniline 3b.
reagent to a solution of the imine in THF at ꢀ78 ꢁC
and then allowing the reaction mixture to warm to
ꢀ42 ꢁC for 3 h. However, addition of vinylmagnesium
chloride required higher temperatures and longer reac-
tion times (ether, reflux, 20 h). In addition to the second-
ary amines, we prepared N-methyl substituted amines 8
and 9 via N-alkylation with MeI using LDA as base
(Schemes 1 and 2, Table 2).
Finally, 2-vinylaniline synthesis could be accomplished
both by a Stille and Suzuki coupling, either starting
from o-iodoaniline 1 or the corresponding carbamate
2, since the isomerization is not a problem.10 However,
as could be seen in Table 1 (entry 3), the best alternative
was the Stille coupling between o-iodoaniline and vinyl-
tributylstannane with Pd(dba)2 as catalyst in the pres-
ence of PPh3. The substituted secondary anilines 6 and
7 were synthesized by addition of Grignard reagents to
N-benzylideneanilines 5a–c, which were obtained in
nearly quantitative yields by condensation of anilines
3a–c with benzaldehyde. The reactions with allylmagne-
sium chloride were carried out by adding the Grignard
Scheme 2. Synthesis of secondary and tertiary anilines.
Table 2. Grignard reagents addition to imines 5a–c N-alkylation
Entry
1
Amine
R1
R2
Product
Yield (%)
71
5a
8a
2
3
4
5
5b
5a
5a
5c
8b
9a
9b
9c
61
79
53
72

U. Martı´nez-Estı´balez et al. / Tetrahedron Letters 48 (2007) 2919–2922
2921
9a did not cyclize. Finally, amine 8a was subjected to
first- and second-generation Grubbs’ catalysts under re-
flux of dichloromethane, and benzazocine 1413 was ob-
tained in 68% and 61% yields, respectively.14 Besides,
although the formation of nitrogen heterocycles, mainly
eight-membered rings, often requires the use of more
expensive second-generation Grubbs’ or Molybdenum
catalysts, in our case the first-generation Grubbs’ cata-
lyst has turned out to be the best (Table 3, Scheme 3).
Figure 1. First- and second-generation Grubbs’ catalysts.
In conclusion, we have demonstrated that the palla-
dium-catalyzed arylation may be combined with nucleo-
philic addition to imines, and ring-closing metathesis to
provide a general approach to 2-phenyl substituted
quinoline, benzazocine, and benzazepine derivatives,
that could compete with previously reported strate-
gies.15 It should be noted that RCM has proven to be
an efficient method for the direct construction, not only
of six- and seven-membered azabicycles, but also of the
more challenging heterocyclic eight-membered rings
from the appropriate acyclic precursors.
Scheme 3. Ring-closing metathesis of substituted anilines 8–9.
Table 3. Ring-closing metathesis of substituted anilines 8–9
Entry Amine Catalyst
Time (h) Product Yield (%)
Acknowledgments
1
2
3
4
5
6
7
8
9
9b
9b
9c
9c
8b
9a
9a
8a
8a
10 (8%)a
11 (8%)a
10 (8%)c
11 (8%)d
10 (8%)d
40
40
64
20
48
12
12
12
12
13
—
—
14
14
75
40b
8
14e
75
—
—
68
61
Financial support from MEC (CTQ2006 01903/BQU)
´
and Universidad del Paıs Vasco is gratefully acknowl-
edged. We also thank the Gobierno Vasco for a Grant
(U.M.-E.).
10 (20%)d 40
11 (20%)a 46
10 (8%)a
11 (8%)a
40
40
References and notes
a Three portions of the catalyst were added at 0, 16, and 27 h.
b Conversion: 75%.
c Four portions of the catalyst were added at 0, 12, 24, and 36 h.
d Two portions of the catalyst were added at 0 and 8 h.
e Conversion: 50%.
1. For selected reviews, see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413–4450; (b) Schrock, R. R.
Tetrahedron 1999, 55, 8141–8153; (c) Phillips, A. J.; Abell,
A. D. Aldrichim. Acta 1999, 32, 75–89; (d) Furstner, A.
¨
Angew. Chem., Int. Ed. 2000, 39, 3012–3043; (e) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29; (f)
Grubbs, R. H. Handbook of Metathesis; Wiley: New York,
2003; (g) Connon, S. J.; Blechert, S. Angew. Chem., Int.
Ed. 2003, 42, 1900–1923; (h) Grubbs, R. H. Tetrahedron
2004, 60, 7117–7140; (i) Deiters, A.; Martin, S. F. Chem.
Rev. 2004, 104, 2199–2238; (j) Donohoe, T. J.; Orr, A. J.;
Bingham, M. Angew. Chem., Int. Ed. 2006, 45, 2664–2670;
(k) Michaut, A.; Rodriguez, J. Angew. Chem., Int. Ed.
2006, 45, 5740–5750; (l) Schrock, R. R. Angew. Chem., Int.
Ed. 2006, 45, 3748–3759; (m) Grubbs, R. H. Angew.
Chem., Int. Ed. 2006, 45, 3760–3765.
With these precursors in hand, we undertook the ring-
closing metathesis experiments (Table 3, Scheme 3). As
it could be expected,11 when we examined RCM of
secondary amines 6 and 7 and screened first and sec-
ond-generation Grubbs’ catalysts 10 and 11 unreacted
starting material was always recovered (see Fig. 1).
However, we were pleased to find that the six-membered
ring precursor 9b (Table 3, entries 1, 2) underwent ring
closure after heating under CH2Cl2 reflux for 12 h, using
8 mol % first-generation Grubbs’ catalyst (the reaction
2. For selected reviews, see: (a) Hoveyda, A. H. Top.
Organomet. Chem. 1998, 1, 105–132; (b) Hoveyda, A.
H.; Schrock, R. R. Chem. Eur. J. 2001, 7, 945–950; (c)
Hoveyda, A. H.; Schrock, R. R. Compr. Asymmetric
Catal., Suppl. 2004, 1, 207–233.
3. For two recent reviews, see: (a) Martin, S. F. Pure Appl.
Chem. 2005, 77, 1207–1212; (b) Nicolaou, K. C.; Bulger, P.
G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527.
4. For some representative examples of our work in this area,
see: (a) Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa,
M. J.; Lete, E. J. Org. Chem. 1997, 62, 2080–2092; (b)
Osante, I.; Collado, M. I.; Lete, E.; Sotomayor, N. Eur. J.
Org. Chem. 2001, 1267–1277; (c) Ruiz, J.; Sotomayor, N.;
Lete, E. Org. Lett. 2003, 5, 1115–1117; (d) Osante, I.; Lete,
E.; Sotomayor, N. Tetrahedron Lett. 2004, 45, 1253–1256;
1
was monitored by TLC and H NMR). 2-Phenyldihy-
droquinoline 12 was isolated in good yields (75% and
40%, respectively).12 However, with amine 9c as sub-
strate, the yield dropped to the 8% when the same cata-
lyst was used; the reaction was sluggish and no starting
material could be recovered. The yield only could be in-
creased to 14% (50% conversion) using second-genera-
tion Grubbs’ catalyst. To obtain the seven-membered
cyclic amine, the use of Grubbs catalyst 10 for the
RCM of amine 8b operating at 40 ꢁC for 68 h (entry
5) gave an optimal result and benzazepine 13 was iso-
lated in 75% yield. In contrast, with the same catalyst,
and also with the second-generation Grubbs’ catalyst,
´
(e) Gonzalez-Temprano, I.; Osante, I.; Lete, E.; Soto-
mayor, N. J. Org. Chem. 2004, 69, 3875–3885; (f) Ruiz, J.;

2922
U. Martı´nez-Estı´balez et al. / Tetrahedron Letters 48 (2007) 2919–2922
Ardeo, A.; Ignacio, R.; Sotomayor, N.; Lete, E. Tetra- 10. In the Suzuki coupling, the 2,4,6-trivinylcyclotriboroxane
´
hedron 2005, 61, 3311–3324; (g) Garcıa, E.; Arrasate, S.;
was prepared in situ by reaction of vinylmagnesium
chloride and B(OMe)3 as described in: Kerins, F.; O’Shea,
D. F. J. Org. Chem. 2002, 67, 4968–4971.
Lete, E.; Sotomayor, N. J. Org. Chem. 2005, 70, 10368–
10374; (h) Garcıa, E.; Lete, E.; Sotomayor, N. J. Org.
´
Chem. 2006, 71, 6776–6784; (i) Ruiz, J.; Lete, E.;
Sotomayor, N. Tetrahedron 2006, 62, 6182–6189.
11. Pandit, U. K.; Overkleeft, H. S.; Bore, B. C.; Bieraugel, H.
Eur. J. Org. Chem. 1999, 959–968, see also Refs. 1c and 5a.
12. For examples of unsubstituted, or 2-alkyl substituted
dihydroisoquinolines synthesis by RCM, see: (a) Van
Otterlo, W. A. L.; Pathak, R.; de Koning, C. B. Synlett
2003, 1859–1861; (b) Theeraladanon, C.; Arisawa, M.;
Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2005,
16, 827–831; (c) Arisawa, M.; Terada, Y.; Takahashi, K.;
Nakagawa, M.; Nishida, A. J. Org. Chem. 2006, 71, 4255–
5. For a review on approaches to nitrogen heterocycles using
RCM, see: (a) Arisawa, M.; Tereda, Y.; Theeraladanon,
C.; Takahashi, K.; Nakagawa, M.; Nishida, A. J. Orga-
nomet. Chem. 2005, 690, 5398–5406; For recent examples,
see: (b) Felpin, F. X.; Girard, S.; Wo-Thanh, G.; Robins,
R. J.; Villiers, J.; Lebreton, J. J. Org. Chem. 2001, 66,
6305–6312; (c) Dolman, S. J.; Sattely, E. S.; Hoveyda, A.
H.; Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991–
6997; (d) Chippindale, A. M.; Davies, S. G.; Iwamoto, K.;
Parkin, R. M.; Smethurst, C. A. P.; Smith, A. D.;
´
4261; (d) Bennasar, M. L.; Roca, T.; Monerris, M.; Garcıa-
´
Dıaz, D. J. J. Org. Chem. 2006, 71, 7028–7034, For the
preparation of the C-4 substituted derivatives, see: Ref. 4a.
13. Synthesis of 1-methyl-2-phenyl-1,2,3,6-tetrahydrobenzo[b]-
azozine (14). A solution of amine 8a (174 mg, 0.63 mmol)
in dry CH2Cl2 (15 mL) was treated with first-generation
Grubb’s catalyst 10 (3 · 0.04 mg, 8 mol %) under reflux
for 40 h. The second and third portions of the catalyst
were added after heating for 16 h and 27 h, respectively.
The reaction mixture was allowed to reach rt. Removal of
the solvent under reduced pressure, followed by flash
column chromatography (silica gel, 5% hexane/AcOEt)
afforded benzazozine 14 (106 mg, 68%): IR (CHCl3)
´
Rodrıguez-Solla, H. Tetrahedron 2003, 59, 3253–3265;
(e) Dolman, S. J.; Hultzsch, K. C.; Pezet, F.; Teng, X.;
Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2004,
126, 10945–10953; (f) Sattely, E. S.; Cortez, G. A.;
Moebius, D. C.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 8526–8533; (g) Dondas, H. A.;
Clique, B.; Cetinkaya, B.; Grigg, R.; Kilner, C.; Morris, J.;
Sridharan, V. Tetrahedron 2005, 61, 10652–10666; (h)
Brass, S.; Gerber, H.-D.; Do¨rr, S.; Diederich, W. E.
Tetrahedron 2006, 62, 1777–1786.
6. This work has been presented in part in the ‘XIV
1594 cmꢀ1 1H NMR (CDCl3) 1.89–2.01 (m, 1H), 2.25–
;
´
Congreso Nacional de la Sociedad Espanola de Quımica
˜
Terapeu´tica’, Bilbao (Spain), 2005, com.C-65.
2.32 (m, 1H), 2.63 (s, 3H), 3.27–3.36 (dd, J = 17.0, 6.3 Hz,
1H), 3.91–4.01 (m, 2H), 5.25–5.31 (m, 1H), 5.77–5.86 (m,
1H), 7.12–7.47 (m, 9H); 13C NMR (CDCl3) 31.7, 36.4,
40.5, 72.9, 122.3, 124.6, 125.1, 126.8, 127.4, 127.8, 128.0,
130.1, 131.2, 137.3, 142.7, 151.8; MS (EI) [m/z (rel
inensity)] 249 (M+, 100), 208 (12), 172 (32), 158 (27), 144
(9). HRMS calcd for C18H19N: 249.1517, found: 249.1530.
7. The carbamate 2 was prepared by treatment of o-iodo-
aniline 1 with ethyl chloroformate and pyridine in THF at
room temperature for 16 h (90%).
8. Organ, M. G.; Xu, J.; N’Zemba, B. Tetrahedron Lett.
2002, 48, 8177–8180.
9. Synthesis of 2-allylaniline (3a). To a solution of methyl 2-
iodophenylcarbamate 2 (297 mg, 1.07 mmol) in dry DMF
(10 mL), allyltributylstananne (0.41 mL, 1.29 mmol), and
Pd(PPh3)4 (250 mg, 0.21 mmol) were added under argon
atmosphere. The reaction mixture was heated at 100 ꢁC
for 18 h and then allowed to reach room temperature. The
solvent was evaporated under reduced pressure, and the
residue was dissolved in CH2Cl2 (15 mL) and washed with
brine (3 · 15 mL). The organic extracts were dried
(Na2SO4) and concentrated in vacuo. Flash column
chromatography (silica gel, 10% hexane/AcOEt) afforded
aniline 3a (65 mg, 47%) as an oil: IR (CHCl3) 3447,
14. For the synthesis of a dihydrobenzazepine and a
dihydrobenzazocine derivative by RCM, see: Arisawa,
M.; Theeraladanon, C.; Nishida, A.; Nakagawa, M.
Tetrahedron Lett. 2001, 42, 8029–8033.
15. 2-Phenylquinolines have been synthesized by addition of
organometallics to quinoline: (a) Crawforth, C. E.; Meth-
Cohn, O.; Russell, C. A. J. Chem. Soc., Perkin Trans. 1
1972, 2807–2810; (b) Goldstein, S. W.; Dambek, P. J.
Synthesis 1989, 221–222; Thermal cyclization of 2-azahexa-
trienes: (c) Hibino, S.; Sugino, E. Heterocycles 1987, 26,
1883–1889; Carbonylation of 20-nitrochalcones and 20-
nitrostyrenes catalyzed by palladium: (d) Tollari, S.;
Penoni, A.; Cenini, S. J. Mol. Catal. A 2000, 152, 47–54;
2-Phenylbenzo[b]azepines have been prepared by intermo-
lecular allene-nitrone cycloadditions: (e) Tufariello, J. J.;
Ali, S. A.; Klingele, H. O. J. Org. Chem. 1979, 44, 4213–
4215; Ring expansion reaction of tetrahydronaphthalene
derivatives: (f) Adam, G.; Andrieux, J.; Plat, M. Tetra-
hedron 1982, 38, 2403–2410.
3368 cmꢀ1 1H NMR (CDCl3) 3.36 (d, J = 6.3 Hz, 2H),
;
3.67 (broad s, 2H), 5.12–5.20 (m, 2H), 5.93–6.09 (m, 1H),
6.72 (d, J = 7.9 Hz, 1H), 6.81 (t, J = 7.4 Hz), 7.09–7.16
(m, 2H); 13C NMR (CDCl3) 36.1, 115.5, 115.8, 118.5,
123.6, 127.2, 129.8, 135.7, 144.6; MS (EI) [m/z (rel
inensity)] 133 (M+, 100), 118 (36), 106 (29), 77 (9). HRMS
calcd for C9H11N: 133.0891, found: 133.0888.