Facile synthesis of medium-sized cyclic amines based on Friedel-Crafts reaction via iminium cation by use of acetylene dicobalt complex

Article abstract of DOI:10.1016/j.tetlet.2007.07.128

An intramolecular Friedel-Crafts reaction of N-methoxymethyl sulfoneamides 3e-j containing an acetylene dicobalt moiety was found to proceed smoothly to afford eight- and nine-membered cyclic amines 4e-j in high yields.

Full text of DOI:10.1016/j.tetlet.2007.07.128

Tetrahedron Letters 48 (2007) 7228–7231
Facile synthesis of medium-sized cyclic amines based on
Friedel–Crafts reaction via iminium cation by use of
acetylene dicobalt complex
Megumi Mizukami,a Hiroshi Saito,a Toshio Higuchi,a Masanori Imai,a
Hideo Bando,a Norio Kawaharaa and Shinji Nagumob,*
aHokkaido Pharmaceutical University, School of Pharmacy, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan
bKogakuin University, Department of Applied Chemistry, 2665-1 Nakano-machi, Hachioji, Tokyo 192-0015, Japan
Received 26 May 2007; revised 13 July 2007; accepted 19 July 2007
Available online 27 July 2007
Abstract—An intramolecular Friedel–Crafts reaction of N-methoxymethyl sulfoneamides 3e–j containing an acetylene dicobalt moi-
ety was found to proceed smoothly to afford eight- and nine-membered cyclic amines 4e–j in high yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Nature abounds with compounds containing eight- or
nine-membered cyclic amine as a prominent architec-
tural feature and showing significant biological activities.
Such compounds include buflavine,1a balasubramide,1b
manzamines,1c moschamide,1d securamine A,1e neo-
dihydrothebaine1f and rhazinilam (Fig. 1).1g Despite
numerous advances in the field of synthetic organic
chemistry, the development of general and efficient
strategies for the construction of these ring systems
remains as a significant challenge. Pictet–Spengler reac-
tion, which is regarded as Friedel–Crafts (FC) reaction
of iminium cation, is well known as an efficient method
to prepare tetrahydroisoquinoline derivatives.2 Such a
method was also applicable to the construction of se-
ven-membered cyclic amines.3 However, there have been
few reports on construction of eight- and nine-membered
cyclic amines based on this method.3f–h We thus
describe herein FC cyclization of N-methoxymethyl sul-
foneamides 1 into eight-membered cyclic amines via
iminium cations. The installation of an acetylene dico-
balt moiety often makes the formation of a medium-
sized cyclic compound easier since the moiety takes a
bended conformation which looks like cis-olefin.4 Fur-
thermore, unlike cis-olefin, an acetylene dicobalt is
stable to acid. Thus, we also report an intramolecular
FC reaction of N-methoxymethyl sulfoneamides 3 with
an acetylene dicobalt moiety (Fig. 2).
Me
O
Me
N
N
MeO
MeO
N
H
OH
Buflavine
Balasubramide
N
H
OMe
OH
N
H
H
O
OH
H
O
N
O
NH
NH
H
O
N
H
Moschamide
Manzamine A
MeO
HO
N
NH
O
N Me
N
N
N
H
N
Br
Cl
Me
Me H
MeO
Neodihydrothebaine
Rhazinilam
Securamine A
Figure 1. Natural products containing eight- or nine-membered cyclic
amines.
N-Methoxymethyl sulfoneamide 1 was prepared as
shown in Scheme 1. Sonogashira coupling of
*
Corresponding author. E-mail: bt13071@ns.kogakuin.ac.jp
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.128

M. Mizukami et al. / Tetrahedron Letters 48 (2007) 7228–7231
7229
converted intoN-methoxymethyl sulfoneamides 1a–f5
by tosylation and the subsequent catalytic hydrogena-
tion and introduction of a MOM group.
R
Ts
N
R
MOM
N
Ts
1
2
Table 1 summarizes the FC reaction of N-methoxym-
ethyl sulfoneamide. Treatment of 1a with 0.5 equiv of
trimethylsilyltriflate (TMSOTf) at room temperature
gave the eight-membered cyclic amine 2a5 in 58% yield
after 29 h (Table 1, entry 1). The effect of an electron-
releasing group on the reactivity was examined. The
presence of a methyl group on a benzene ring increased
the reaction rate. Sulfoneamides 1b–d with one or two
methyl groups on aromatic rings were converted into
the corresponding cyclic amines in excellent yields with-
in 10–30 min by treatment with TMSOTf (entries 2–4).
In entry 2, both regioisomers 2b and 2b0 were obtained.
Surprisingly, introduction of a methoxyl group, which is
a stronger electron-releasing group than a methyl group,
caused the decomposition to lower the yield of the de-
sired compounds 2e and 2f (entries 5 and 6). Also treat-
ment of the isolated 2f with TMSOTf gave the complex
mixture. The decomposition of 2e and 2f by treatment
with TMSOTf might be attributed to the fission of the
C1-N2 bond, which is nearly parallel to the p-orbital
of the benzene ring. Probably, methoxyl groups on the
benzene ring should facilitate the bond cleavage. Since
cyclic amines having a methoxyl group on the benzene
ring were found to be instable to TMSOTf, which is a
strong Lewis acid, we carried out the FC reaction of
1f by using a mild Lewis acid. As a result, La(OTf)3 pro-
moted the cyclization of 1f moderately to afford 2f in
58% yield after 24 h.
MOM
Ts
n
R
N
R
N
Ts
n
(OC) Co
Co(CO)
3
(OC) Co
Co(CO)
3
3
3
4
3
Figure 2.
bromobenzenes 5a–f and 3-butyn-1-ol gave alcohols
6a–f5 in high yields.6 Mesylation of 6a–f followed by
the sequence of substitution with sodium azide and
reduction with Ph3P afforded amines 7a–f,7 which were
R
3
R
3
R
R
2
a
R
2
OH
1
Br
R
1
5a-f
6a-f
R
3
R
2
b, c, d
e, f, g
NH
2
R
1
7a-f
R
3
R
R
2
R3
MOM
R3
MOM
R2
R1
N Ts
R2
R1
N
a,b
1
Ts
n
Ts
1a-f
N
H
n
(OC)3Co
Co(CO)3
7e-h (n = 1)
7i-j (n = 2)
Scheme 1. Reagents and conditions: (a) 3-butyn-1-ol, (Ph3P)2PdCl2,
CuI, Et3N, 70 ꢁC, 80–100%; (b) MsCl, Et3N, CH2Cl2, rt, 87–98%; (c)
NaN3, DMF, 60 ꢁC, 89–100%; (d) Ph3P, THF, H2O, 60 ꢁC, 91–100%;
(e) TsCl, DMAP, pyridine, rt, 78–100%; (f) 20% Pd(OH)2–C, H2,
MeOH or AcOEt, rt, 91–100%; (g) MOMCl, NaH, THF, rt, 80–100%.
3e-h (n = 1)
3i-j (n = 2)
Scheme 2. Reagents and conditions: (a) MOMCl, NaH, THF, rt, 97–
100%; (b) Co2(CO)8, CH2Cl2, rt, 89–100%.
Table 1.
Ts
R3
R3
N
R2
R2
R1
Lewis acid
CH2Cl2, rt
MOM
N
R1
Ts
1a-f
2a-f, b', e'
Entry
Substrates
R1
R2
R3
Lewis acid
Time
Products
Yield (%)
1
2
3
4
5
6
7a
1a
1b
1c
1d
1e
1f
H
Me
Me
Me
OMe
OMe
OMe
H
H
H
Me
H
H
H
Me
H
H
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
La(OTf)3
29 h
2a
2b + 2b0 (R1 = R2 = H, R3 = Me)
2c
58
30 min
10 min
10 min
10 min
10 min
24 h
94 (2b:2b0 = 9:1)
93
94
2d
2e + 2e0 (R1 = R2 = H, R3 = OMe)
2f
2f
11 (2e:2e0 = 9:1)
H
H
OMe
OMe
2
58
1f
a In entry 7, 1f was also recovered in 14% yield.

7230
M. Mizukami et al. / Tetrahedron Letters 48 (2007) 7228–7231
Table 2.
MOM
Ts
N
R3
R3
N Ts
R2
R1
R2
R1
TMSOTf
n
n
CH2Cl2, rt
(OC)3Co Co(CO)3
(OC)3Co Co(CO)3
3e-i
4e-i, e', h'
Entry
Substrates
R1
R2
R3
n
Time (min)
Products
Yield (%)
1
2
3
4
5
6
3e
3f
3g
3h
3i
OMe
OMe
OMe
OMe
OMe
OMe
H
H
OMe
H
OMe
H
H
OMe
H
Me
H
OMe
1
1
1
1
2
2
20
15
10
10
10
10
4e + 4e0 (R1 = R2 = H, R3 = OMe)
4f
4g
4h + 4h0 (R1 = Me, R2 = H, R3 = OMe)
4i
4j
86 (4e:4e0 = 4:1)
95
88
81 (4h:4h0 = 2:1)
84
81
3j
Next, we carried out an intramolecular FC reaction of
N-methoxymethyl sulfoneamides 3 with an acetylene
dicobalt moiety. Compounds 3e–i5 were prepared by
alkylation with methoxymethyl chloride followed by
treatment of 7e–i5 with Co2(CO)8 (Scheme 2).
Acknowledgement
This work was supported by a Grant-in-Aid for Scien-
tific Research (C) (15590017 to S.N.).
Interestingly, the presence of cobalt complexes was
found to increase the stabilization of cyclic amine with
methoxyl groups on the aromatic ring (Table 2). Treat-
ment of 3e–h with TMSOTf in CH2Cl2 afforded eight-
membered cyclic amine 4e–h5 in high yields (Table 2,
entries 1–4). The presence of dicobalt moiety in
2-benzazocines might prevent the C1–N2 bond from
taking the orientation parallel to the p-orbital of the
benzene ring. Also cyclization of 3i–j proceeded
smoothly to give the corresponding nine-membered
cyclic amine 4i–j5 (entries 5 and 6). The dicobalt moieties
of 4f–j were successfully removed by reduction with
n-Bu3SnH to produce 8f–j5 in high yields (Scheme 3).8
References and notes
1. (a) Viladomat, F.; Bastida, J.; Codina, C.; Campbell, W. E.;
Mathee, S. Phytochemistry 1995, 40, 307; (b) Riemer, B.;
Hofer, O.; Greger, H. Phytochemistry 1997, 45, 337; (c)
Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J. Am.
Chem. Soc. 1986, 108, 6404; (d) Sarker, S. D.; Dinan, L.;
Sik, V.; Underwood, E.; Waterman, P. G. Tetrahedron Lett.
1998, 39, 1421; (e) Rahbaek, L.; Anthoni, U.; Christopher-
sen, C.; Nielsen, P. H.; Petersen, B. O. J. Org. Chem. 1996,
61, 887; (f) Bentley, K. W. J. Am. Chem. Soc. 1967, 89,
2464; (g) Banerji, A.; Majumder, P. L.; Chatterjee, A.
Phytochemistry 1970, 9, 1491.
2. Review for the Pictet–Spengler reaction: (a) Cox, E. D.;
Cook, J. M. Chem. Rev. 1995, 95, 1797; (b) Hino, T.;
Nakagawa, M. Heterocycles 1998, 49, 499.
3. (a) Wittekind, R. R.; Lazarus, S. J. Heterocycl. Chem. 1971,
8, 495; (b) Marson, C. M.; Pink, J. H. Tetrahedron Lett.
1995, 36, 8107; (c) Merriman, G. H.; Fink, D. M.; Freed, B.
S.; Kurys, B. E.; Pavlek, S.; Varriano, J.; Paulus, E. F.
Synlett 2000, 137; (d) Martins, J. C.; Rompaey, K. V.;
In conclusion, an intramolecular Friedel–Crafts reaction
of the iminium cation derived from N-methoxymethyl
sulfoneamide was found to be an efficient method to
generate eight-membered cyclic amines. A methyl group
on a benzene ring was a good electron-releasing group
to promote this reaction. However, the presence of a
methoxyl group on a benzene ring resulted in decompo-
sition of the corresponding cyclic amine. Introduction of
a cobalt complex to the side chain of the substrates was
found to suppress the decomposition. Further extension
of these reactions is in progress.
´
Wittmann, G.; To¨mbo¨ly, C.; Toth, G.; Kimpe, N. D.;
´
Tourwe, D. J. Org. Chem. 2001, 66, 2884; (e) Marson, C.
M.; Pink, J. H.; Hall, D. J. Org. Chem. 2003, 68, 792; (f)
Orazi, O. O.; Corral, R. A.; Giaccio, H. J. Chem. Soc.,
Perkin Trans. 1 1986, 1977; (g) Rabi-Barakay, A.; Ben-
Ishai, D. Tetrahedron 1994, 50, 10771; (h) Kim, H. J.;
Yoon, U. C.; Jung, Y. S.; Park, N. S.; Cederstrom, E. M.;
Mariano, P. S. J. Org. Chem. 1998, 63, 860.
4. For recent examples: (a) Jamison, T. F.; Shambayati, S.;
Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119,
4353; (b) Iwasawa, N.; Satoh, H. J. Am. Chem. Soc. 1999,
121, 7951; (c) Takai, S.; Isobe, M. Org. Lett. 2002, 4, 1183;
(d) Tanino, K.; Kondo, F.; Shimizu, T.; Miyashita, M. Org.
Lett. 2002, 4, 2217; (e) Kira, K.; Hamajima, A.; Isobe, M.
Tetrahedron 2002, 58, 1875; (f) Teobald, B. J. Tetrahedron
2002, 58, 4133; (g) Tanino, K.; Onuki, K.; Asano, K.;
Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.
J. Am. Chem. Soc. 2003, 125, 1498; (h) Young, D. G. J.;
Burlison, J. A.; Peters, J. J. Org. Chem. 2003, 68, 3494; (i)
Baba, T.; Takai, S.; Sawada, N.; Isobe, M. Synlett 2004,
603; (j) Ortega, N.; Martin, T.; Martin, V. S. Org. Lett.
2006, 8, 871; (k) DiMartino, J.; Green, J. R. Tetrahedron
2006, 62, 1402; (l) Inaba, K.; Takaya, J.; Iwasawa, N.
Ts
N
R3
Ts
N
R3
R2
R1
n
-Bu3SnH
R2
R1
n
benzene, 60 °C
n
(OC)3Co
(R1 = R3 = OMe, R2 = H, n = 1)
4g (R1 = R2 = OMe, R3 = H, n = 1)
4h (R1 = OMe, R2 = H, R3 = Me, n = 1) 8h (87%)
Co(CO)3
(80%)
8g (74%)
4f
8f
4i (R1 = R3 = OMe, R2 = H, n = 2)
4j (R1 = R2 = OMe, R3 = H, n = 2)
8i (87%)
8j (88%)
Scheme 3.

M. Mizukami et al. / Tetrahedron Letters 48 (2007) 7228–7231
7231
Chem. Lett. 2007, 36, 474, references cited therein; See also
(m) Yet, L. Chem. Rev. 2000, 100, 2963.
190; HR-MS m/z calcd for C20H23NO4S: 373.1348, found:
373.1343. 1H NMR (400 MHz): d 7.73 (2H, d, J = 8.2 Hz),
7.28 (2H, d, J = 8.2 Hz), 6.37 (1H, d, J = 12.2 Hz), 6.34
(1H, d, J = 2.4 Hz), 6.26 (1H, d, J = 2.4 Hz), 5.78 (1H, dt,
J = 12.2, 5.9 Hz), 4.49 (2H, s), 3.79 (3H, s), 3.71 (3H, s),
3.34–3.28 (2H, m), 2.42 (3H, s), 2.34–2.27 (2H, m). 13C
NMR (100 MHz): d 160.09 (C), 159.37 (C), 142.71 (C),
140.15 (C), 137.31 (C), 131.63 (CH), 129.34 (CH · 2),
127.87 (CH), 127.34 (CH · 2), 114.05 (C), 104.06 (CH),
97.60 (CH), 55.42 (CH3), 55.27 (CH3), 42.74 (CH2), 42.08
(CH2), 29.89 (CH2), 21.47 (CH3). Anal. Calcd for
C20H23NO4S: C, 64.32; H, 6.21; N, 3.75. Found: C, 64.03;
H, 6.21; N, 3.64.
5. All new compounds gave spectroscopic data in agreement
with assigned structures. Representative data are shown
below. Compound 4f: IR (neat, cmꢀ1) 3450, 3024, 2056.
SIMS-POSI m/z 657 (M+), 573; HR-SIMS calcd for
C26H21Co2NO10S: 656.9550, found: 656.9603. 1H NMR
(270 MHz): d 7.72 (2H, d, J = 8.2 Hz), 7.27 (2H, d,
J = 8.2 Hz), 6.77 (1H, d, J = 2.3 Hz), 6.42 (1H, d,
J = 2.3 Hz), 4.30 (2H, s), 3.88 (3H, s), 3.82 (3H, s), 3.67
(2H, t, J = 5.6 Hz), 3.31 (2H, t, J = 5.6 Hz), 2.42 (3H, s).
13C NMR (100 MHz): d 199.46 (C · 6), 160.31 (C), 158.21
(C), 143.21 (C), 139.06 (C), 135.85 (C), 129.43 (CH · 2),
127.57 (CH · 2), 118.07 (C), 109.82 (CH), 98.79 (CH),
95.83 (C), 91.29 (C), 56.07 (CH3), 55.23 (CH3), 50.19 (CH2),
43.32 (CH2), 36.46 (CH2), 21.49 (CH3). Compound 8f
6. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 50, 4467.
7. Taylor, E. C.; Pont, J. L. Tetrahedron Lett. 1987, 28, 379.
8. Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39,
2609.
(white crystal): mp 132–134 ꢁC (AcOEt). IR (KBr, cmꢀ1
3448, 3014, 2936, 1319, 1158. EI-MS m/z 373 (M+), 218,
)