Acid-mediated cyclizations of SEM-protected heterocyclic anilines and adjacent hydroxyls or enol-ethers

Article abstract of DOI:10.1016/j.tetlet.2013.09.059

Acid-mediated cyclizations of SEM-protected heterocyclic anilines and adjacent hydroxyls or enol ethers during SEM deprotection are reported. Strategies to suppress these side reactions and their potential synthetic utilities are also described.

Full text of DOI:10.1016/j.tetlet.2013.09.059

Tetrahedron Letters 54 (2013) 6373–6377
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Acid-mediated cyclizations of SEM-protected heterocyclic anilines
and adjacent hydroxyls or enol-ethers
⇑
Zhaoyang Meng , Binyuan Sun, Panduranga Adulla Reddy, M. Arshad Siddiqui
Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Acid-mediated cyclizations of SEM-protected heterocyclic anilines and adjacent hydroxyls or enol ethers
during SEM deprotection are reported. Strategies to suppress these side reactions and their potential syn-
thetic utilities are also described.
Received 3 September 2013
Accepted 14 September 2013
Available online 21 September 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
SEM
Acid-mediated cyclization
Dihydrooxazine
Piperidin-4-one
[2-(Trimethylsilyl)ethoxy]methyl (SEM) has been frequently
used as a protecting group for alcohols (primary, secondary, and
tertiary),1 heterocyclic NHs (indazole,2 imidazole,3 pyrazole,4 in-
dole, and pyrrole5), (hetero)aryl amines (primary6 and secondary7),
and the nitrogen of amides8 and sulfonamides.9 In some cases, the
SEM group not only temporarily masks the reactive sites but also
functions as a directing group for metalation.5
In general, the SEM group could be cleanly cleaved from sub-
strates with acid or fluoride anion. However, there are several re-
ports that when refluxing in MeOH or other alcohols in the
presence of catalytic amounts of HCl, some SEM-protected com-
pounds could be transformed to the corresponding MOM-pro-
tected derivatives or related alkoxyaminals based on the alcohols
used.10 In our research, we observed that some SEM-protected het-
erocyclic anilines might involve in ring formation side reactions
with adjacent functional groups, such as hydroxyls or enol-ethers,
during the acidic deprotection process. Herein, we report this
interesting reactivity of the SEM group. Strategies to suppress
these side reactions and their potential synthetic utilities are also
described.
duced by NaBH4 to the corresponding primary alcohol 2, the
desired alcohol 5 was not observed when 2 was treated with
50% TFA/H2O to remove the 8-amino’s bis-SEM protecting
groups.11 Instead, 2 was cleanly converted to an unexpected ma-
jor product 3 which showed a molecular ion peak at m/z 436
(M+H)+, 12 higher than the calculated value of 5.12 This suggested
that compared to 5, 3 has an extra carbon atom present in the
molecule. We proposed that this specific carbon atom was from
one of the SEM protecting groups and 3 had the 2,4-dihydro-
1H-pyrazolo[50,10:2,3]pyrimido[4,5-d][1,3]oxazine core structure.
Indeed, the 1H NMR spectra exhibits characteristic features of this
structure: singlet at 5.01 ppm and doublet at 5.03 ppm corre-
sponding to the two CH2 groups of the dihydrooxazine ring. The
tricyclic structure assignment was further confirmed through de-
tailed 2D NMR studies (Fig. 1).
The originally targeted 5 was eventually made by reversing the
reaction sequence, with the SEM deprotection performed prior to
the aldehyde reduction as shown in Scheme 1.13
A similar ring closure reaction was observed when the diol
analog 6 was treated with HCl to provide 7 as shown in
Scheme 2.11
As part of the same drug discovery program, we also targeted
ketone 9, which we planned to prepare from the SEM-protected
enol ether 8 by acid treatment as demonstrated in Scheme 3. Inter-
estingly, we found that the product of this step was highly depen-
dant on the acid used.13,14 Ketone 9 was obtained as expected
when using 50% TFA/H2O as the acid; however, the unexpected
10 was isolated when switching to a non-aqueous acid, such as
During the course of a medicinal chemistry program, we
planned to prepare compound 5 for testing and the initial syn-
thetic route is outlined in Scheme 1. After aldehyde 1 was re-
⇑
Corresponding author at present address: Merck Research Laboratories, 770
Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. Tel.: +1 215 652 6199.
E-mail address: zhaoyang.meng@merck.com (Z. Meng).
Present address: Paraza Pharma Inc., 500 Boulevard Cartier (West), Laval, Quebec
H7V 5B7, Canada.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.059

6374
Z. Meng et al. / Tetrahedron Letters 54 (2013) 6373–6377
N
N
N
50% TFA/H2O
O2S
O2S
N
N
69%
NaBH4
MeOH
N
N
N
X
O
NH
3
OH N(SEM)2
2
69%
N
N
N
N
N
O2S
O2S
O2S
NaBH4
MeOH
N
N
N
50% TFA/H2O
71%
N
N
N
N
61%
O
NH2
4
O
N(SEM)2
1
OH NH2
5
Scheme 1. Preparation of 3 and 5.
neat TFA or 20% TFA/CH2Cl2.15 Similar to the previous case shown
in Scheme 1, the molecular weight difference between 9 and 10
was 12. We suspected that a piperidin-4-one ring was formed
involving the bis-SEM protecting groups and the adjacent enol
ether group. The tricyclic core structure of 10, 8,9-dihydropyrazol-
o[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one, was confirmed by ex-
tended 2D NMR studies (Fig. 2).
A plausible mechanism of these SEM group involved cyclization
reactions is described in Scheme 4. Upon acid treatment, SEM-pro-
tected heterocyclic anilines 2 and 8 are converted to hemaminals 30
and 100, respectively, which could be further transformed to
the corresponding iminium intermediate 300 and 1000. Both
N
O2S
N
5.01
63.2
94.4
N
N
142.5
NH
5.03
73.2
O
Figure 1. Selected 1H and 13C chemical shifts and HMB correlation of 3.
O
O
N
N
HO
O
HCl
N
N
62%
N
N
N
N
HO
HO
O
NH
7
OH N(SEM)2
6
Scheme 2. Preparation of 7.
N
O2S
N
N
50% TFA/H2O
N
N
O2S
81%
O
NH2
9
N
N
N
EtO
N
O2S
20% TFA/CH2Cl2
N(SEM)2
N
78%
N
8
O
N
NH
10
Scheme 3. Preparation of 9 and 10.

Z. Meng et al. / Tetrahedron Letters 54 (2013) 6373–6377
6375
in Scheme 5, their general synthetic routes include: (a) reductive
cyclization of 1-(2-nitro-phenyl)-2-propen-1-one 11 using iron
powder in concentrated HCl;18 (b) Friedel–Crafts cyclization of 3-
(phenylamino)propanoic acid 12 in hot polyphosphoric acid
(PPA) or hot methanesulfonic acid;19 (c) acid catalyzed Fries rear-
rangement of 1-arylazetidin-2-one 13.20
We considered that the ring formation strategy involving the
SEM group and a neighboring enol ether group had the potential
to be an alternative method of preparing important piperidin-4-
ones and related structures. As listed in Table 1, a series of
substrates with different substituents were submitted to TFA
treatment. To our delight, all reactions provided the tricyclic
systems in moderate to high yield.14
In summary, we have identified unknown cyclizations be-
tween SEM-protected heterocyclic anilines and adjacent hydrox-
yls or enol-ethers. While these side reactions could be limited
through altering the reaction sequence or reaction conditions,
these ring formation strategies have proved to be synthetically
useful as demonstrated by a variety of examples with different
substituents. Further developments in this area will be reported
in due course.
N
N
O2S
N
96.7
150.1
O
N
9.51
189.9
gCOSY (scalar)
HMBC 3-bond
NH
3.78
38.5
2.74
36.6
Figure 2. Selected 1H and 13C chemical shifts and gCOSY/HMBC correlation of 10.
hemiaminals 30 and 100 react consecutively with the neighboring
hydroxy or enol ether via proton catalysis to afford the two tricy-
clic analogs, 3 and 10, respectively in high yield. Alternatively, 3
and 10 could also be considered as generated by an intramolecular
addition of the adjacent hydroxy or enol ether to the iminium
double bond in intermediate 300 and 1000.
Piperidin-4-one and its related analogs are common features in
a number of natural products16 and versatile intermediates in the
preparation of a range of pharmaceutical active agents.17 As shown
N
N
N
N
O2S
O2S
O2S
TFA
R =
TFA
EtO
N
N
N
N
R =
N
O
EtO
N
N
N
N
3'
OH
R
NH
OH
OH NH
OH
O
10'
Me3Si
SiMe3
R =
R =
2
8
OH
EtO
N
N
O2S
O2S
N
N
N
N
EtO
N
N
OH NH
N
N
N
N
NH
3"
O2S
O2S
10"
N
N
N
O
N
O
NH
3
NH
10
Scheme 4. Proposed mechanism.
a) Fe
conc. HCl
100oC
NO2
83%
O
O
H
N
c) TFA
refluxing
N
11
80%
13
H
b) PPA
120oC
N
O
14
OH
80%
O
12
Scheme 5. Known synthetic routes of piperidin-4-one and analogs.

6376
Z. Meng et al. / Tetrahedron Letters 54 (2013) 6373–6377
Table 1
Acid-mediated cyclization of SEM-protected heterocyclic anilines and enol-ethers
R2
R2
R1
N
R1
N
20% TFA/CH2Cl2
O
N
N
EtO
N
N
NH
N(SEM)2
15
16
Entry
SEM protected substrates 15
Products 16
Yield (%)
N
N
O2S
O2S
1
72
N
N
N
N
EtO
N
O
N
N
NH
N
N(SEM)2
15a
16a
N
N
BocN
HN
2
85
N
N
EtO
N
O
N
N
NH
N
N(SEM)2
15b
16b
N
N
O2S
EtO
O2S
O2S
3
4
5
75
99
80
N
N
N
O
O
N
N
N
N
15c
N(SEM)2
NH
16c
F
F
N
O2S
EtO
N
N
N
N
N
N
N
N
15d
16d
N(SEM)2
NH
N
N
BocN
EtO
HN
H
H
N
N
N
N
O
N
N
N(SEM)2
16e
15e
NH
N
N
N
O
O
6
7
84
68
N
N
N
N
EtO
N
O
N
N
N(SEM)2
15f
NH
16f
N
N
O
O
N
N
N
N
EtO
N
N
N(SEM)2
O
N
N
NH
15g
16g
Acknowledgments
References and notes
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Z. Meng et al. / Tetrahedron Letters 54 (2013) 6373–6377
6377
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1H, J = 8.43 Hz), 7.97 (d, 1H, J = 8.14 Hz), 7.77 (t, 1H, J = 7.65 Hz), 7.69 (t, 1H,
J = 7.53 Hz), 5.03 (d, 2H, J = 3.10 Hz), 5.01 (s, 2H), 3.38 (dd, 2H, J = 13.64,
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15. Representative procedure for the synthesis of piperidin-4-one derivatives:
preparation of 5-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-(quinolin-3-
yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one (10). At 0 °C,
TFA (1 mL) was added in one portion to 8 (36.9 mg, 0.051 mmol). The mixture
was slowly warmed up to room temperature and stirred at the same
temperature for 1 h. Concentration and purification by RP-HPLC (20–80%
CH3CN/H2O with 0.1% TFA) provided 10 (22.2 mg, 78%). 1H NMR (DMSO-d6) d:
(ppm)) 9.82 (d, 1H, J = 2.16 Hz), 9.51 (s, 1H), 9.09 (s, 1H), 9.03 (s, 1H), 8.05 (d,
1H, J = 8.37 Hz), 7.99 (d, 1H, J = 8.15 Hz), 7.79 (t, 1H, J = 7.63 Hz), 7.69 (t, 1H,
J = 7.51 Hz), 4.18 (tt, 1H, J = 10.52, 3.62 Hz), 3.78 (ddd, 2H, J = 7.44, 2.60 Hz),
3.34 (ddd, 2H, J = 14.16, 43.58 Hz), 3.26 (dd, 2H, 14.16, 3.54 Hz), 2.74 (t, 2H,
J = 7.29 Hz), 2.35 (dt, 2H, J = 12.27), 2.28 (br obs, 2H). 13C NMR (DMSO-d6) d:
(ppm) 189.9, 164.1, 150.1, 147.8, 144.2, 144.0, 143.7, 131.5, 129.5, 128.0, 128.0,
127.7, 127.6, 125.8, 106.2, 96.7, 50.5, 39.4, 38.5, 36.6, 28.9. HRMS calcd for
[M+H]: 448.1418. Found: 448.1438.
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12. Representative procedure for the synthesis of dihydrooxazine derivatives:
preparation of 4-(7-(quinolin-3-yl)-2,4-dihydro-1H-pyrazolo[50,10:2,3]
pyrimido[4,5-d][1,3]oxazin-5-yl)tetrahydro-2H-thiopyran 1,1-dioxide (3). At
0 °C, 2 (21 mg, 0.031 mmol) was treated with 50% TFA/H2O (1 mL). The mixture
was slowly warmed up to room temperature and stirred at the same
temperature overnight. Concentration and purification by RP-HPLC (20–80%
CH3CN/H2O with 0.1% TFA) provided 3 (11.7 mg, 69%). 1H NMR (DMSO-d6) d:
(ppm)) 9.86 (d, 1H, J = 2.12 Hz), 9.16 (s, 1H), 9.05 (s, 1H), 8.90 (s, 1H), 8.04 (d,