Synthesis of heterocycles based on rhodium-catalyzed C-H amination

Article abstract of DOI:10.1055/s-0033-1340159

A new stereoselective approach to substituted pyrrolidines and piperidines is described that involves Du Bois' C-H -amination reaction, Boc-activation of a cyclic sulfamate group, and base-promoted intramolecular cyclization. This methodology can be utilized for the synthesis of tetrahydrofuran and tetrahydrothiophene derivatives. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340159

LETTER
▌133
lSetyternthesis of Heterocycles Based on Rhodium-Catalyzed C–H Amination
Synthesis of Heterocycles by C–H Amination
Keisuke Takahashi, Daisuke Yamaguchi, Jun Ishihara, Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Fax +81(95)8192426; E-mail: susumi@nagasaki-u.ac.jp
Received: 26.08.2013; Accepted after revision: 25.09.2013
tetrahydrofuran (THF) according to the conditions em-
ployed for the synthesis of 3 (Table 1). In this case, the cy-
clized compound 8a was not observed on TLC even after
ten hours.
Abstract: A new stereoselective approach to substituted pyrro-
lidines and piperidines is described that involves Du Bois’ C–H
amination reaction, Boc-activation of a cyclic sulfamate group, and
base-promoted intramolecular cyclization. This methodology can
be utilized for the synthesis of tetrahydrofuran and tetrahydrothio-
phene derivatives.
O
O
O
ClS(=O)2NH2
MeCN, DMA
OH
S
Key word: C–H amination, heterocycle synthesis, rhodium-cata-
lyzed reaction, cyclization
H2N
Ph
Ph
97%
NHCbz
4
NHCbz
5
Developing new methodologies for the synthesis of het-
erocyclic compounds is of great importance in drug dis-
covery, material science, and natural product synthesis.1,2
Recently, we reported the total synthesis of kaitocepha-
lin,3 in which we devised a new methodology to construct
the highly substituted pyrrolidine core through a rhodium-
catalyzed C–H amination4,5 followed by an intramolecular
nucleophilic attack of a nitrogen atom on a sulfamate
group (Scheme 1). Since, to our knowledge, such an
approach to heterocyclic compounds has not been report-
ed,6,7 we became interested in probing the scope and lim-
itations of this particular pyrrolidine synthesis.
O
O
Rh2(OAc)4
(2 mol%)
S
6a: R = H
RN
Boc2O
Et3N, DMAP
CH2Cl2
O
PhI(OAc)2
MgO, CH2Cl2
Ph
7a: R = Boc
NHCbz
80%
84%
Scheme 2 Preparation of cyclic N-Boc-sulfamate 7a
However, when water was added to the mixture, the cycli-
zation occurred instantaneously to give 8a in 59% yield
(Table 1, entry 1). Interestingly, after treatment of 7a with
NaH at 0 °C for 5 min, addition of water (10 equiv) was
found to effectively promote the cyclization to afford 8a
in good yield (entry 2). When the reaction was carried out
in DMF, 8a was obtained in high yield8 and the use of a
large excess of water gave comparable results (entries 3
and 4). It turned out that performing the reaction with 3 M
NaOH (2 equiv) in place of NaH and H2O also brought
about the cyclization effectively, although the reaction be-
came sluggish (entry 5). However, when a large excess of
aqueous NaOH was used, the yield of 8a decreased mark-
edly (entry 6). MeOH could also be employed in place of
water (entry 7), although the use of NaOMe diminished
the yield of 8a (entries 7 and 8). It was also found that no
reaction occurred by using K2CO3 in MeOH at room tem-
O
O
O
O
S
S
Boc2O
OR
Rh(II)
OR
H2N
Ph
O
HN
O
then
NaH, H2O
Ph
Cl3COCHN
Cl3COCHN
1
2
OH
R = p-(MeO)C6H4CH2OCH2
Cl
Cl
OR
BocHN
Ph
N
HO
NH2
O
NH
COCCl3
3
CO2H
HO2C
N
CO2H
H
kaitocephalin
1) TFA, CH2Cl2
2) H2, Pd(OH)2 (20% )
MeOH
H
BocHN
Ph
Scheme 1 The key pyrrolidine synthesis
N
N
3) CDI, DBU
CH2Cl2–toluene (1:1)
reflux
Cbz
Ph
N
H
9
O
8a
To assess the feasibility of our pyrrolidine synthesis, we
first conducted experiments using cyclic N-Boc-sulfamate
7a as a substrate, which was prepared from 4 via 5 and 6a
according to Du Bois’ protocol (Scheme 2).4b Initially, the
cyclization was examined by using NaH (2 equiv) in
38%
O
H
N
H
N
H
H
H
H
SYNLETT 2014, 25, 0133–0137
Advanced online publication: 06.11.2013
NOE
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340159; Art ID: ST-2013-U0820-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 3 Confirmation of the stereochemistry of 8a

134
K. Takahashi et al.
LETTER
Table 1 Base-Promoted Cyclization of 7a
O
O
O
BocHN
Ph
S
conditions
BocN
N
Ph
Cbz
8a
NHCbz
7a
Entry
Conditions
NaH (2 equiv), THF, r.t., 10 h
Yield of 8a (%)a
1
59b
2
NaH (2 equiv), THF, 0 °C, 5 min, add H2O (10 equiv), then r.t., 30 min
NaH (2 equiv), DMF, 0 °C, 5 min, add H2O (10 equiv), then r.t., 5 min
NaH (2 equiv), DMF, 0 °C, 5 min, add H2O (excess),c then r.t., 5 min
3 M NaOH (2 equiv), DMF, r.t., 2 h
78
3
99
4
92
5
94
6
3 M NaOH (20 equiv), DMF, r.t., 2 h
74
7
NaH (2 equiv), DMF, 0 °C, 5 min, add MeOH (10 equiv), then r.t., 5 min
NaOMe (2 equiv), MeOH (20 equiv), DMF, r.t., 10 h
K2CO3 (2 equiv), MeOH, r.t., 5 h
84
8
55
9
no reaction
a Isolated yield.
b Before aqueous workup, cyclized compound 8a was not observed on TLC.
c H2O (1 mL) was used for 7a (0.21 mmol).
perature (entry 9). Although the role of the water is not 1–4). Similarly, benzamide 7e and acetamide 7f afforded
clear, hydrogen bonding interactions are possibly one of the corresponding cyclized products 8e and 8f, respective-
the main factors that influence the reactivity of the pro- ly, in comparable yields (entries 5 and 6).
cess.9 The NOESY spectrum of 9 prepared from 8a con-
firmed the stereostructure of 8a (Scheme 3), thus proving
that the cyclization took place in an SN2 fashion with com-
plete inversion of the stereochemistry.
Based on the optimized reaction conditions, we then eval-
uated the substrate scope (Table 3). First, five substituted
Boc-protected sulfamates 7g–k were prepared from 6g–k
and subjected to cyclization (Method A). It should be
We next explored the effect of various protecting groups stressed that pyrroidines 8g–j as well as piperidine 8k
of the primary amine using the optimized NaH and H2O could be synthesized in moderate overall yields regardless
conditions (Table 2). As a result, in addition to Cbz, Moc, of the substitution pattern, even in the case where a qua-
and Alloc groups, even the sterically demanding Boc ternary center is present near the reaction site (entries 2–
group was found to be suitable for this cyclization (entries 5). Next, step-economical one-pot preparation10 of 8a and
8f–k from 6a and 6f–k was also investigated
(Method B).11 Thus, after confirming the formation of 7a
and 7g–k on TLC, their cyclizations were conducted by
adding NaH (3 equiv) followed by water (10 equiv). We
were pleased to find that this one-pot procedure worked
effectively and, except for 8i, afforded the corresponding
Table 2 Base-Promoted Cyclization of 7a–f
O
O
O
NaH (2 equiv), DMF BocHN
0 °C, 5 min
S
BocN
Ph
Ph
N
then H2O (10 equiv)
X
r.t., 5 min
8a–f
NHX
O
O
O
7a–f
Boc2O, Et3N
DMAP, CH2Cl2
S
BocHN
Ph
HN
Entry
Sulfamate
X
Pyrrolidine Yield of 8 (%)a
then K2CO3, MeOH
X
Ph
12: X = O, 91%
13: X = S, 80%
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
Cbz
Moc
Alloc
Boc
Bz
8a
8b
8c
8d
8e
8f
99
89
77
75
71
80
XAc
10: X = O
11: X = S
O
p-(Br)H4C6
TsHN
Ph
NH
Ph
O
S
14
15
Ac
Scheme 4 Synthesis of tetrahydrofuran 12 and tetrahydrothiophene
a Isolated yield.
13
Synlett 2014, 25, 133–137
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Heterocycles by C–H Amination
135
cyclized products in good yields. In the case of 6i, butoxy- methodology detailed above (Scheme 4). As a result, a
carbonylation did not proceed selectively on the sulfamate one-pot procedure involving butoxycarbonylation of a
nitrogen and the reaction produced several Boc-protected sulfamate and methanolytic removal of the acetyl group
products.
turned out to be operative in these cases, and the cyclized
compounds 12 and 13, respectively, were obtained in
good yields. The stereochemistries of 12 and 13 were un-
We also examined the synthesis of tetrahydrofuran 12 and
tetrahydrothiophene 13 from 10 and 11, based on the
Table 3 Synthesis of 8a,g–k
O
O
O
R
S
YN
BocHN
R
R
n
R
R
Ph
n
Ph
N
R
Cbz
R
R
R
R
NHCbz
8a, 8g–k
6a,g–k: Y = H
7a,g–k: Y = Boc
R = H or Me
Entry
Sulfamate
Yield of 7 (%)a
Product
Yield of 8 (%)a
O
O
O
S
BocHN
Ph
BocN
1
80
99b (81)c
N
Ph
Cbz
NHCbz
8a
7a
O
O
O
S
BocHN
Ph
BocN
2
3
4
5
70
80
39
65
84b (80)c
N
Ph
Cbz
NHCbz
8g
7g
O
O
O
S
BocHN
Ph
BocN
79b (77)c
Ph
N
Cbz
NHCbz
NHCbz
8h
7h
O
O
O
S
BocHN
Ph
BocN
74b (complex mixture)c
N
Ph
Cbz
8i
7i
O
O
O
S
BocHN
Ph
BocN
88b (77)c
N
Ph
Cbz
NHCbz
8j
7j
O
O
O
S
BocN
BocHN
Ph
85b (80)c
Ph
N
6
72
Cbz
CbzHN
8k
7k
a Isolated yield.
b Method A: (1) Boc2O, Et3N-DMAP, CH2Cl2; (2) NaH (2 equiv), DMF, 0 °C, 5 min, then H2O (10 equiv), r.t., 5 min.
c Method B (one-pot): Boc2O, Et3N-DMAP, DMF, then NaH (3 equiv), 0 °C, 5 min, then H2O (10 equiv), r.t., 5 min.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 133–137

136
K. Takahashi et al.
LETTER
(f) Narina, S. V.; Kumer, T. S.; George, S.; Sudalai, A.
Tetrahedron Lett. 2007, 48, 65. (g) Yakura, T.; Sato, S.;
Yoshimoto, Y. Chem. Pharm. Bull. 2007, 55, 1284.
(h) Kang, S.; Lee, H.-K. J. Org. Chem. 2010, 75, 237.
(i) Tanino, T.; Ichikawa, S.; Shiro, M.; Matsuda, A. J. Org.
Chem. 2010, 75, 1366. (j) Tanino, T.; Ichikawa, S.; Matsuda,
A. Org. Lett. 2011, 13, 4028.
ambiguously determined by X-ray crystallographic analy-
sis of their derivatives 1412 and 15.13
In conclusion, the present work provides a new methodol-
ogy for the stereoselective construction of substituted
heterocycles such as pyrrolidines, piperidines, tetrahydro-
furans, and tetrahydrothiophenes utilizing rhodium-cata-
lyzed C–H amination.
(8) Preparation of 8a from 4 via 5, 6a, and 7a; Sulfamate 5:
Formic acid (0.69 mL, 15 mmol) was added to neat
chlorosulfonyl isocyanate (1.3 mL, 15 mmol) at 0 °C and the
mixture was stirred for 5 min. MeCN (10 mL) was added and
the mixture was stirred at r.t. for 8 h to generate sulfamoyl
chloride (1.5 M in MeCN). To an ice-cooled solution of 4
(1.40 g, 4.28 mmol) in DMA (10 mL) and MeCN (10 mL)
was added sulfamoyl chloride (1.5 M in MeCN, 5.7 mL, 8.56
mmol). The mixture was stirred at r.t. for 1 h and saturated
NaHCO3 (5 mL) was added at 0 °C. The mixture was
extracted with EtOAc, washed with brine, dried over
MgSO4, and concentrated in vacuo. Purification of the
residue by column chromatography (SiO2 30 g; hexane–
EtOAc, 4:1 to 1:1) gave 5 (1.70 g, 97%) as a colorless
amorphous solid.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
(A) (22249001) and a Grant-in-Aid for Young Scientists (B)
(23790015) from JSPS, a Grant-in-Aid for Scientific Research on
Innovative Areas ‘Reaction Integration’ (No. 2105) (22106538 and
24106736) from MEXT and The Naito Foundation.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
Cyclic Sulfamate 6a: To a solution of 5 (411 mg, 1.08
mmol) in CH2Cl2 (10 mL) at r.t. were added MgO (100 mg,
2.50 mmol), PhI(OAc)2 (BAIB; 354 mg, 1.12 mmol), and
Rh2(OAc)4 (9 mg, 0.02 mmol). After stirring at r.t. for 2 h,
the mixture was filtered through cotton and concentrated in
vacuo. Purification of the residue by column
chromatography (SiO2 30 g; hexane–EtOAc, 3.5:1 to 1.5:1)
gave 6a (371 mg, 84%) as a colorless amorphous solid.
N-Boc Sulfamate 7a: To a stirred solution of 6a (1.10 g,
0.75 mol) in CH2Cl2 (20 mL) at r.t. were added Et3N (0.59
mL, 4.08 mmol), Boc2O (712 mg, 0.98 mmol), and DMAP
(33 mg, 0.27 mmol). After stirring at r.t. for 5 h, the mixture
was extracted with EtOAc, washed with brine, dried over
MgSO4, and concentrated in vacuo. Purification of the
residue by column chromatography (SiO2 15 g; hexane–
EtOAc, 4:1) gave 7a (1.10 g, 80%) as a colorless amorphous
solid.
Pyrrolidine 8a: To an ice-cooled solution of 7a (100 mg,
0.20 mmol) in DMF (2 mL) was added NaH (60% in mineral
oil, 16 mg, 0.40 mmol). The mixture was stirred at 0 °C for
5 min, then H2O (36 μL, 2.0 mmol) was added and the
mixture was stirred at r.t. for 5 min. The mixture was
neutralized with 1 M HCl, extracted with EtOAc, washed
with sat. NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo. Purification of the residue by column
chromatography (SiO2 5 g; hexane–EtOAc, 5:1) gave 8a (83
mg, 99%) as a colorless solid.
References and Notes
(1) For recent reviews, see: (a) Mihovilovic, M. D.; Stanetty, P.
Angew. Chem. Int. Ed. 2007, 46, 3612. (b) Godoi, B.;
Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937.
(c) Eckert, H. Molecules 2012, 17, 1074. (d) Foster, R. A.
A.; Willis, M. C. Chem. Soc. Rev. 2013, 42, 63.
(e) Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C. Org.
Biomol. Chem. 2013, 11, 191. (f) Zhang, M.; Zhang, A.-Q.;
Peng, Y. J. Organomet. Chem. 2013, 723, 224. (g) Ball, C.
J.; Willis, M. C. Eur. J. Org. Chem. 2013, 425.
(2) For methodologies for heterocycle synthesis recently
developed by our group, see: (a) Takahashi, K.; Haraguchi,
N.; Ishihara, J.; Hatakeyama, S. Synlett 2008, 671.
(b) Takahashi, K.; Midori, M.; Kawano, K.; Ishihara, J.;
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923.
(3) Takahashi, K.; Yamaguchi, D.; Ishihara, J.; Hatakeyama, S.
Org. Lett. 2012, 14, 1644.
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J. J. Am. Chem. Soc. 2001, 123, 6935. (c) Espino, C. G.;
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(9) For related water-promoted displacement reactions, see:
(a) Azizi, N.; Saidi, M. R. Org. Lett. 2005, 7, 3649.
(b) Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189.
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(11) Representative One-Pot Preparation (Method B): Et3N
(0.05 mL, 0.38 mmol), DMAP (3 mg, 0.025 mmol), and
Boc2O (72 mg, 0.33 mmol) were added to a solution of 6a
(100 mg, 0.25 mol) in DMF (2 mL) at r.t. The mixture was
stirred at r.t. for 5 h, then NaH (60% in mineral oil, 30 mg,
0.75 mmol) was added at 0 °C. The mixture was stirred at
0 °C for 5 min, then H2O (45 μL, 2.5 mmol) was added, and
(7) For heterocycle syntheses utilizing Rh-catalyzed C–H
amination, see: (a) Wehn, P. M.; Du Bois, J. J. Am. Chem.
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Synlett 2014, 25, 133–137
© Georg Thieme Verlag Stuttgart · New York

LETTER
the mixture was stirred at r.t. for 5 min. The mixture was
Synthesis of Heterocycles by C–H Amination
137
(12) The crystallographic data (CCDC 943270) can be obtained
free of charge from the Cambridge Crystallographic Data
centre via www.ccdc.cam.ac.uk/data_request/cif.
(13) The crystallographic data (CCDC 943271) can be obtained
free of charge from the Cambridge Crystallographic Data
centre via www.ccdc.cam.ac.uk/data_request/cif.
neutralized with 1 M HCl, extracted with EtOAc, washed
with saturated NaHCO3 and brine, dried over MgSO4, and
concentrated in vacuo. Purification of the residue by column
chromatography (SiO2 5 g; hexane–EtOAc, 5:1) gave 8a (85
mg, 81%) as a colorless solid.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 133–137

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