Preparation of 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine] via an N-sulfonyl Pictet-Spengler reaction

Article abstract of DOI:10.1016/j.tetlet.2006.05.082

A high yielding synthesis of variously substituted 2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine] is reported. N-(2-nitrophenyl)sulfonyl was successfully used as both an activating and protecting group for the key Pictet-Spengler reaction.

Full text of DOI:10.1016/j.tetlet.2006.05.082

Tetrahedron Letters 47 (2006) 5115–5117
Preparation of 2,3-dihydro-1H-spiro[isoquinoline-4,40-piperidine]
via an N-sulfonyl Pictet–Spengler reaction
Jian Liu,* Tianying Jian, Iyassu Sebhat and Ravi Nargund
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 24 April 2006; revised 11 May 2006; accepted 12 May 2006
Available online 6 June 2006
Abstract—A high yielding synthesis of variously substituted 2,3-dihydro-1H-spiro[isoquinoline-4,40-piperidine] is reported. N-(2-
nitrophenyl)sulfonyl was successfully used as both an activating and protecting group for the key Pictet–Spengler reaction.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The privileged structure 1-(methylsulfonyl)-spiro[indo-
line-3,40-piperidine] (1) has proved to be a versatile
building block. Research at Merck & Co. led to the dis-
covery of MK-0677 containing a spiro[indoline-3,40-
piperidine] substructure. The compound is one of the
most potent peptidomimetic growth hormone secreta-
gogues and entered Phase III clinical trials.1 The SAR
study about structure 1 directed our interest to the (2-
methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,40-
piperidine] (2) containing an expanded six member ring.
Given its potential for biological activity, an efficient
method for its preparation was required (Fig. 1).
preparation of 1,2,3,4-tetrahydroisoquinoline deriva-
tives from phenyl ethylamine. The reaction tolerates
some electron-withdrawing substitutions on the phenyl
ring when the amine is activated by acyl or sulfonyl
groups.4 Here we report the preparation of 2,3-dihy-
dro-1H-spiro[isoquinoline-4,40-piperidine] utilizing an
N-sulfonyl Pictet–Spengler reaction to construct the iso-
quinoline ring.
As outlined in Scheme 1, the commercially available 4-
cyano-4-phenyl piperidine (3) was used as the starting
material for the synthesis. The piperidine nitrogen was
initially protected as the Boc derivative, the nitrile was
then reduced to the primary amine with the borane–
THF complex and activation was achieved by forming
the methanesulfonamide. Pictet–Spengler cyclization of
the phenylethyl sulfonamide (4) with formaldehyde in
a mixture of acetic acid and sulfuric acid (4:1) provided
an excellent yield of 10-Boc-(2-methylsulfonyl)-2,3-dihy-
dro-1H-spiro[isoquinoline-4,40-piperidine] (2) after the
Boc reprotection.5 The phenylethyl acetamide under-
went the Pictet–Spengler reaction very slowly at elevated
A modestly yielding preparation of the dimethoxy
substituted
2,3-dihydro-1H-spiro[isoquinoline-4,40-
piperidine] has been reported.2 The synthesis uses a
Schmidt reaction of spiro[indane-3,40-piperidine]-1-one
followed by reduction of the formed lactam. Pictet–
Spengler cyclization3 has been commonly used for the
H
P
N
P
N
N
O
NH2
O
N
O
Boc
N
Boc
N
O
S
H
N
N
O
S
N
O
N
S
a, b, c
d, e
O
O
O
CN
O
S
O
S
2
HN
N
1
MK-0677
P = H or Boc
3
4
O
2
O
Figure 1.
Scheme 1. Synthesis of 2. Reagents and conditions: (a) Boc2O, NaOH
(5 N), THF, 95%; (b) BH3–THF, 40 ꢁC; (c) MeSO2Cl, TEA, CH2Cl2,
90% (two steps); (d) (CH2O)n, AcOH–H2SO4 (4:1); (e) Boc2O, NaOH
(5 N), EtOAc, 99% (two steps).
*
Corresponding author. Tel.: +1 732 594 9600; fax: +1 732 594
3007; e-mail: jian_liu@merck.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.082

5116
J. Liu et al. / Tetrahedron Letters 47 (2006) 5115–5117
Table 1. Product substitutions and yields for Pictet–Spengler reaction
Me
N
P
N
Products
R1
R2
P
Yield (%)a
R1
R2
9a
9b
9c
9d
9e
9f
H
H
H
H
F
Me
Me
Me
F
Cl
MeO
F
Me
Cl
EtOCO
Bocb
Cbz
EtOCO
Bocb
97
65
52
61
96
36
82
R1
R2
R1
R2
b
CN
a
CN
CN
6(a-g)
7(a-g)
5(a-g)
EtOCO, Boc, Cbz
P =
P
N
Cbz
Bocb
P
N
9g
a Separated yield.
e
c,d
R1
R2
R1
R2
b Boc was reattached after Pictet–Spengler reaction.
O
S
O
N
HN
S
O
O
9(a-g)
8(a-g)
P
N
P
Scheme 2. Synthesis of 9 with different substitutions on the phenyl ring.
N
O
Reagents and conditions: (a) MeN (CH2CH2Cl)2ÆHCl, Bu4NþHSOꢀ,
4
H
R3
R1
R2
NaOH (50%), 20–70%; (b) ethylchloroformate, ClCH2CH2Cl, 85 ꢁC, or
1-chloroethylchloro formate, ClCH2CH2Cl, 85 ꢁC, then MeOH, Boc2O
or CbzCl, NaOH (5 N) 70–85%; (c) BH3–THF, 40 ꢁC; (d) MeSO2Cl,
TEA, CH2Cl2, rt, 90% (two steps); (e) (CH2O)n, AcOH–H2SO4 (4:1),
then NaOH (5 N), Boc2O when P = Boc.
R1
R2
O
N
O
AcOH/H2SO4
HN
S
S
O
O
R3
10
8
Scheme 3. Pictet–Spengler reaction with different aldehydes.
reaction temperature and provided a very low yield
(<20%) of the spiro structure.
Table 2. Summary for the Pictet–Spengler reaction with different
We then investigated the effect of different aryl substitu-
tions on the Pictet–Spengler reaction (Scheme 2).
Commercially available or readily prepared 4- or 3,4-
substituted phenylacetonitriles (5a–g) were converted
to N-methyl-4-cyano-4-phenyl piperidines (6a–g) by
double alkylation with N-methyl-bis(2-chloroethyl)
amine under basic, phase-transfer conditions.6 Elec-
tron-donating substitutions on the phenyl ring slowed
down the reaction and gave much lower yields [e.g. 4-
methoxyphenyl acetonitrile (20% yield) and 3,4-dimeth-
oxyphenyl acetonitrile (no product obtained)]. The
N-methyl on the piperidine was removed and trans-
formed to ethoxy, t-butoxy (Boc) or benzyloxy (Cbz)
carbonyl group (7a–g). Subsequent reduction of the nitr-
iles with borane–THF complex followed by conversion
of the resultant amines to their methanesulfonamides
(8a–g) generated the key cyclization precursors. The
methanesulfonamides were subjected to the Pictet–Spen-
gler reaction to provide moderate to excellent yields of
spiro[isoquinoline-4,40-piperidine] structures. The 3,4-
disubstituted phenyl substrates provided mostly regio-
selective products on the sterically less hindered position
(>12:1 selectivity as monitored by 1H NMR of the crude
product). The yields for these reactions are listed in
Table 1. The cyclization is accelerated with electron-
donating groups. The Boc group was removed under
acidic reaction conditions and needed to be reattached.
The loss of small portion of Cbz protection was
observed, consequently leading to low yield when no
reprotection was applied. The ethoxy carbonyl was
untouched.
aldehydes
Products
R1
R2
R3
T (ꢁC)
Yield (%)a
10a
10b
10c
10d
10e
10f
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Cl
Me
Et
Ph
Me
Et
0
98b
15b
61b
44c
63c
56b
40
80
0
40
rt
Me
a Isolated yield.
b The N-protection was ethoxy carbonyl.
c The N-protection was Cbz.
Reactions with benzaldehyde and propionaldehyde
needed elevated reaction temperature. No reaction was
detected with isobutyraldehyde presumably because of
serious steric hindrance. With an electron-withdrawing
group on the aromatic ring, such as in 8b (F) and 8c
(Cl), the Pictet–Spengler reaction only occurred with
formaldehyde. Table 2 summarizes these data.
For ease of further derivatization we also explored alter-
native protecting/activating groups that would allow
selective deprotection of the piperidine and isoquinoline
nitrogens. Given its ease of removal under mild condi-
tions, we investigated the cyclization of compound 11
containing Fukuyama’s 2-nitrophenyl sulfonamide7
(Scheme 4). We discovered that the reaction took place
with high yield of 12. The 2-nitrophenyl sulfonyl group
could be selectively removed with lithium hydroxide and
mercaptoacetic acid without affecting the Boc protecting
group. On the other hand, treatment with HCl in diox-
ane, effected the Boc protection leaving the sulfonyl
group intact.
Different aldehydes were also used in the Pictet–Spengler
reaction in order to investigate their activity (Scheme 3).
The reactivity sequence is formaldehyde > acetalde-
hyde > benzaldehyde > propionaldehyde. Acid catalyzed
polymerization of acetaldehyde complicated the trans-
formation and low reaction temperature was required.
In summary, we have demonstrated that the biologically
interesting (2-methylsulfonyl)-2,3-dihydro-1H-spiro[iso-
quinoline-4,40-piperidine] can be prepared via an N-sul-

J. Liu et al. / Tetrahedron Letters 47 (2006) 5115–5117
5117
4. (a) Lazarus, S.; Wittekind, R. R. J. Heterocycl. Chem. 1971,
8, 495; (b) Mollow, M. M.; Venkov, A. P. Synthesis 1978,
62; (c) Lukanov, L. K.; Venkov, A. P.; Mollv, N. M.
Synthesis 1987, 204; (d) Venkov, A. P.; Lukanov, L. K.
Synthesis 1989, 59; (e) Comins, D. L.; Badawi, M. M.
Tetrahedron Lett. 1991, 32, 2995; (f) Zinczuk, J.; Sorokin, I.
H.; Orazi, O. O.; Corral, R. A. J. Heterocycl. Chem. 1992,
29, 859; (g) Kohno, H.; Sekine, Y. Heterocycles 1996, 42,
141; (h) Kohno, H.; Yamada, K. Heterocycles 1999, 51,
103; (i) Silveira, C. C.; Bernardi, C. R.; Braga, A. L.;
Kaufman, T. S. Tetrahedron Lett. 1999, 40, 4969; (j) Ran,
C.; Wang, G.; Wu, T.; Xie, M. Synth. Commun. 2000, 30,
1581; (k) Cho, S.-D.; Song, S.-Y.; Hur, E.-J.; Chen, M.;
Joo, W.-H.; Falck, J. R.; Yoon, Y.-J.; Shin, D.-S. Tetra-
hedron Lett. 2001, 42, 6251.
5. Procedure for the preparation of 2 (Pictet–Spengler reac-
tion): A 25 mL one neck round bottom flask was charged
with 4 (341 mg, 0.925 mmol), paraformaldehyde (83 mg,
2.78 mmol) and acetic acid (1.6 mL). The mixture was
stirred for 10 min and then cooled to 0 ꢁC in an ice-water
bath. Concentrated sulfuric acid (0.4 mL) was added
dropwise over 5 min. The resulting reaction mixture was
stirred at 0 ꢁC for 20 min and at room temperature for a
further 1 h. The mixture was then cooled to 0 ꢁC in ice-
water bath, diluted with ethyl acetate (20 mL) and
quenched with NaOH (5 N) until pH ꢁ 9. Boc2O (303 mg,
1.39 mmol) was added and the reaction mixture was stirred
for 30 min at room temperature. After the organic layer was
separated, the aqueous layer was extracted with ethyl
acetate (3 · 10 mL). The combined organic phases were
washed by water, brine, dried over MgSO4, filtered and
concentrated. The crude material was then purified by
MPLC (12 M, 0–40% ethyl acetate in hexanes) to afford
0.350 g product 2 (99%, rf = 0.3 by ethyl acetate:hex-
anes = 2:3): Formula: C19H28N2O4S (380.18); LC–MS:
(M+H)+: 381.2; 1H NMR (500 MHz, CDCl3, ppm,
t = 25 ꢁC): d 7.37 (d, J = 7.5 Hz, 1H), 7.27 (t, J = 8 Hz,
1H), 7.20 (t, J = 7.3 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 4.45
(br, 2H), 4.09 (br, 2H), 3.70 (br, 1H), 3.31 (br, 1H), 3.00 (br,
2H), 2.91 (s, 3H), 2.10 (br, 1H), 1.86 (br, 1H), 1.75 (br, 2H),
1.48 (s, 9H).
Boc
N
Boc
N
c,d
a,b
R1
R2
R1
R2
NO2
O
S
CN
HN
O
11
7
Boc
Boc
N
N
e
R1
R2
R1
R2
NO2
O
S
N
N
O
13
12
Scheme 4. Pictet–Spengler reaction with 2-nitrophenyl sulfonamide.
R1, R2 = H, H; H, Me; Me, Cl. Reagents and conditions: (a) BH3–
THF, 40 ꢁC; (b) 2-nitrophenyl sulfonyl chloride, TEA, CH2Cl2 (80–
90% two steps) (c) (CH2O)n, AcOH–H2SO4 (4:1); (d) Boc2O, NaOH,
EtOAc (>90%, two steps); (e) HSCH2COOH, LiOH, DMF.
fonyl Pictet–Spengler reaction. This methodology allows
for a variety of different substitutions on the phenyl ring
and works with various aldehydes. The N-2-nitrophenyl
sulfonamide can be used in place of methane sulfon-
amide and allows for easy, selective deprotection of
either nitrogen for further derivatization.
References and notes
1. (a) Patchett, A. A.; Nargund, R. P.; Tata, J. R.; Chen,
M.-H.; Barakat, K. J.; Johnston, D. B. R.; Cheng, K.;
Chan, W. W.-S.; Butler, B.; Hickey, G.; Jacks, T.; Schleim,
K.; Pong, S.-S.; Chaung, L.-Y. P.; Chen, H. Y.; Frazier, E.;
Leung, K. H.; Chiu, S.-H. L.; Smith, R. G. Proc. Natl.
Acad. Sci. U.S.A. 1995, 92, 7001; (b) Nargund, R. P.;
Patchettt, A. A.; Bach, M. A.; Murphy, M. G.; Smith, R.
G. J. Med. Chem. 1998, 41, 3103.
6. (a) Kagi, H.; Miescher, K. Helv. Chim. Acta 1949, 323,
2489; (b) Cammack, T.; Reeves, P. C. J. Heterocycl. Chem.
1986, 23, 73.
7. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373.
2. Bernye, D.; Jauner, T. Helv. Chim. Acta 1975, 58, 74.
3. Whaley, W. M.; Govindachari, H. D. Org. React. 1951, 6,
151.