One-pot synthesis of N-heterocycles by tandem carbamoylation-oxidative bromolactamization of ω-alkenylmagnesium bromide

Article abstract of DOI:10.1016/j.tetlet.2013.06.002

An addition reaction of ω-alkenylmagnesium bromide with p-toluenesulfonyl isocyanate and consecutive oxidative cyclization with iodobenzene diacetate afforded brominated lactams in one-pot. An imine was also applicable to a one-pot synthesis of terminally brominated cyclic amine.

Full text of DOI:10.1016/j.tetlet.2013.06.002

Tetrahedron Letters 54 (2013) 4313–4315
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Tetrahedron Letters
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One-pot synthesis of N-heterocycles by tandem carbamoylation–
oxidative bromolactamization of
x-alkenylmagnesium bromide
b
a
a
a
Yasutomo Yamamoto a, , Yuji Takahama , Misa Shimizu , Ai Ohara , Akari Miyawaki ,
⇑
Kiyoshi Tomioka a,
⇑
a Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe 610-0395, Japan
b Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An addition reaction of
x-alkenylmagnesium bromide with p-toluenesulfonyl isocyanate and consecutive
Received 7 May 2013
Revised 28 May 2013
Accepted 4 June 2013
Available online 10 June 2013
oxidative cyclization with iodobenzene diacetate afforded brominated lactams in one-pot. An imine was
also applicable to a one-pot synthesis of terminally brominated cyclic amine.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
One-pot
Hypervalent iodine
Oxidative cyclization
Grignard reagent
Heterocycles
The addition reaction of nitrogen nucleophiles with a carbon–
carbon multiple bond (i.e., hydroamination) is a very powerful car-
bon–nitrogen bond forming reaction.1 Our studies have been
aimed at chiral diether-mediated asymmetric conjugate addition
reactions of lithium amides with enoates.2 An intramolecular ver-
sion of the amination reaction is an effective process for the syn-
thesis of nitrogen-containing heterocycles, and we previously
reported a chiral bisoxazoline–lithium amide-catalyzed asymmet-
ric intramolecular hydroamination of aminoalkene.3 In these reac-
tions, in situ-generated highly reactive lithium amides were used
as nitrogen nucleophiles to react with a C@C double bond, giving
the aminolithiation product. An addition reaction of organometal-
lic reagents with a C@N double bond is an alternative protocol to
prepare nucleophilic metal amide, whose reaction with an intra-
molecular carbon–carbon multiple bond allows for the synthesis
of nitrogen-containing heterocycles in one pot.4 This approach is
highly advantageous in that stepwise synthesis of the cyclization
precursor for heterocycles is unnecessary. Herein we report a
sium amide 3a, which no longer reacted at this stage probably
due to the low nucleophilicity of metal amide toward olefin, and
amide 5a was obtained quantitatively after quenching with aque-
ous ammonium chloride (scheme 1). Oxidation of anionic species
to radical or cationic species is an important umpolung methodol-
ogy for changing the reactivity of anionic intermediates, and it is
potentially useful for combination with anionic cascade reactions.5
In fact, in situ oxidation of 3a with 2 equiv of PhI(OAc)2 in dichlo-
roethane (DCE) gave bromolactam 4a in 55% yield and 5a in 40%
yield.4 Increasing the amount of PhI(OAc)2 to 4 equiv gave 4a in
83% yield (Scheme 1 and Table 1, entries 1 and 2). The same trans-
formation to 4a could be achieved with the addition of 2 equiv bro-
mine or NBS to a solution of 3a as a Br+ source.6
Bromolactamization of amide 5a itself did not proceed at all
with NBS or bromine/NaHCO3, which resulted in the recovery of
5a as shown in Scheme 2. On the other hand, once 5a was con-
verted to the corresponding lithium amide 6a with n-BuLi, subse-
quent treatment with bromine gave cyclized 4a in 76% yield.
These results clearly show that the cyclization step requires the
activation of nitrogen nucleophiles as magnesium- or lithium
amides, such as 3a or 6a, and the one-pot process, in which reac-
tion of 1a with 2 gave ‘activated’ magnesium amide 3a, has an
advantage over the stepwise process.
one-pot addition reaction of
x-alkenylmagnesium bromide with
a C@N double bond–bromolactamization tandem reaction by the
oxidation of an anionic intermediate as a key step.
A reaction of 3-butenylmagnesium bromide 1a with N-tosyliso-
cyanate 2 in THF for 0.5 h at 0 °C gave the corresponding magne-
The reaction conditions were optimized by the examination of
various oxidants (Table 1). The powerful hypervalent iodine oxi-
dant PhI(OCOCF3)2 afforded 4a in moderate (65%) yield (entry 3).
CAN and DDQ gave 4a in 45% and 48% yield, respectively (entries
⇑
Corresponding authors. Tel.: +81 774 65 8676; fax: +81 774 65 8658.
E-mail addresses: yayamamo@dwc.doshisha.ac.jp (Y. Yamamoto), tomioka@
pharm.kyoto-u.ac.jp (K. Tomioka).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.002

4314
Y. Yamamoto et al. / Tetrahedron Letters 54 (2013) 4313–4315
Ts
N
Ts
N
i.
C
Ts
Ts
C
2
Br
Br
Br
Ts
Ts
O
O
2
+
aq NH4Cl
N
NH
N
MgBr
NH
BrMg
+
O
O
O
O
ii.
THF
BrMg
0 °C, 0.5 h
A: PhI(OAc)2
1b
4b
7b
19%
25%
1a
3a
5a
B
: NBS
A: 66%
B: 43%
quant
Ts
N
Ts
N
Ts
NH
PhI(OAc)2 4 eq
O
Br
5a
BrMg
O
O
Br
Br
DCE
i.
Br
rt, 1 h
4a
83%
+
ii.
trace
Br2 2 eq
rt, 2.5 h
1c
1d
4c
7c
0%
0%
4a
80%
A
B
94%
:
: 97%
NBS 2 eq
rt, 0.5 h
Ts
Ph
Ts
Ph
Br
Br
4a
94%
N
NH
i.
+
BrMg
O
Br
O
ii.
Ph
Scheme 1. Tandem carbamoylation–oxidative bromolactamization of 3-butenyl-
magnesium bromide 1a with isocyanate 2.
4d
7d
A: 81%
0%
B: 56%
32%
Table 1
Screening of oxidants
Scheme 3. Carbamoylation–oxidative bromolactamization of Grignard reagents
1b–d.
Ts
N
i.
C
O
2
Ts
N
THF
0 °C, 0.5 h
Ts
Ts
N
NH
BrMg
C
OAc
O
Ts
Ts
O
Br
Ph
O
2
+
PhI(OAc)2
ii.
oxidant
temp, time
N MgBr
N Mg
1a
Br
I
+
4a
5a
O
O
BrMg
OAc
8
1a
Entry Oxidant/equiv
Temp (°C) Time (h) 4a % Yield 5a % Yield
3a
1a
2a
3b
4b
5
6
7
8
9
PhI(OAc)2/2
PhI(OAc)2/4
PhI(OCOCF3)2/4
CAN/4
DDQ/4
aq H2O2/4
H2O2–urea/2
H2O2–(Ph3PO)2/4 rt
mCPBA/1.1
mCPBA/5
rt
rt
rt
rt
rt
rt
rt
1
1
1
1
1
3
2
1
1
2
1
55
83
65
45
48
2
18
42
64
58
63
40
Trace
27
20
38
69
68
45
30
Ts
N
OAc
Mg
Ts
N
O
Br
O
Br
9a
4a
+ PhI
Ts
MgOAc
Ph
Ts
Ph
0
0
rt
2
+
N
N
10
11
35
23
O
Br
O
(PhCO2)2/4
BrMg
Ph
Br
a
1d
9d
4d
DCE was used as a co-solvent in the oxidation step.
b
MeCN was used as a co-solvent in the oxidation step.
Scheme 4. Plausible reaction mechanism.
the yield remained only moderate (entries 7 and 8). mCPBA at
1.1 equiv afforded 4a in 64% yield, but increasing the amount of
mCPBA to 5 equiv did not improve the yield (entries 9 and 10).
Benzoyl peroxide, which does not have acidic protons, gave a yield
(63%) similar to that of mCPBA (entry 11). Thus, oxidative bromo-
lactamization was mediated by various types of oxidants, and
4 equiv of PhI(OAc)2 was optimal.
The applicability of other Grignard reagents was also examined
(Scheme 3). Carbamoylation of 4-pentylmagnesiumbromide 1b
with 2, followed by PhI(OAc)2-mediated cyclization (method A)
gave the 6-exo-cyclization product 4b and dibromide 7b in 66%
and 19% yield, respectively. The NBS-mediated protocol (method
B) afforded a decreased yield (43%) of 4b and an increased yield
(25%) of undesired 7b. Styryl magnesium bromide 1c gave five-
membered lactam 4c in excellent yield (94% with method A and
97% with method B). When Grignard reagent 1d having (E)-olefin
was used, trans-6-endo cyclized product 4d was obtained in 81%
yield by method A. Method B gave a considerable amount of
non-cyclized, dibrominated product 7d (32%) as well as cyclized
NaHCO3 aq. 1.1 eq
Br2 1.1 eq
Ts
no
recovery
NH
reaction
of 5a
O
CH2Cl2/H2O
rt, 7 h
5a
Ts
Ts
n-BuLi 1.2 eq
Br2 1.2 eq
N
Li
N
5a
O
Br
O
THF
rt, 1 h
0 °C, 0.5 h
6a
4a
76%
Scheme 2. Bromolactamization of 5a.
4 and 5). An aqueous solution of H2O2 was incompatible due to the
protonation of magnesium amide intermediate 3a by water to give
5a, whose subsequent cyclization did not proceed (entry 6 and
Scheme 2). Anhydrous hydrogen peroxide, H2O2–urea, and H2O2–
(Ph3PO)2 complex, led to better results than aqueous H2O2, but

Y. Yamamoto et al. / Tetrahedron Letters 54 (2013) 4313–4315
4315
4-tol
N
References and notes
i.
Ts
N
Ts
10a
PhI(OAc)2
BrMg
BrMg
4-tol
1. Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108,
3795–3892.
Br
ii.
1a
1c
2. (a) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc. 2003,
125, 2886–2887; (b) Doi, H.; Sakai, T.; Yamada, K.; Tomioka, K. Chem. Commun.
2004, 1850–1851; (c) Sakai, T.; Doi, H.; Kawamoto, Y.; Yamada, K.; Tomioka, K.
Tetrahedron Lett. 2004, 45, 9261–9263; (d) Sakai, T.; Kawamoto, Y.; Tomioka, K.
J. Org. Chem. 2006, 71, 4706–4709; (e) Sakai, T.; Doi, H.; Tomioka, K. Tetrahedron
2006, 62, 8351–8359; (f) Harada, S.; Sakai, T.; Takasu, K.; Yamada, K.;
Yamamoto, Y.; Tomioka, K. Chem. Asian J. 2012, 7, 2196–2198; (g) Harada, S.;
Sakai, T.; Takasu, K.; Yamada, K.; Yamamoto, Y.; Tomioka, K. J. Org. Chem. 2012,
77, 7212–7222; (h) Harada, S.; Sakai, T.; Takasu, K.; Yamada, K.; Yamamoto, Y.;
Tomioka, K. Tetrahedron 2013, 69, 3264–3273.
11a
68%
cis/trans 1/1
Ts
N
Ph
N
i.
Ts
Ph
10b
Br
ii.
PhI(OAc)2
3. Ogata, O.; Ujihara, A.; Tsuchida, S. T.; Kaneshige, A.; Tomioka, K. Tetrahedron
Lett. 2007, 48, 6648–6650; (b) Tsuchida, S.; Kaneshige, A.; Ogata, T.; Baba, H.;
Yamamoto, Y.; Tomioka, K. Org. Lett. 2008, 16, 3635–3638; (c) Ogata, T.;
Kimachi, T.; Yamada, K.; Yamamoto, Y.; Tomioka, K. Heterocycles 2012, 86, 469–
485.
11b
52%
cis/trans 1/3
4. A one-pot synthesis of brominated cyclic imine using alkenyl carbonitriles,
Grignard reagents, and PhI(OAc)2 was reported. (a) Sanjaya, S.; Chiba, S.
Tetrahedron 2011, 67, 590–596; Related cascade reactions: (b) Sanjaya, S.;
Chua, S. H.; Chiba, S. Synlett 2012, 1657–1661; (c) Tnay, Y. L.; Chen, C.; Chua, Y.
Y.; Zhang, L.; Chiba, S. Org. Lett. 2012, 14, 3550–3553.
5. (a) Jahn, U.; Müller, M.; Aussieker, S. J. Am. Chem. Soc. 2000, 122, 5212–5213;
(b) Jahn, U. Chem. Commun. 2001, 1600–1601; (c) Jahn, U.; Rudakov, D. Synlett
2004, 1207–1210; (d) Goddard, J.-P.; Gomez, C.; Brebion, F.; Beauvière, S.;
Fensterbank, L.; Malacria, M. Chem. Commun. 2007, 2929–2931; (e) Kamimura,
A.; Kadowaki, A.; Yoshida, T.; Takeuchi, R.; Uno, H. Chem. Eur. J. 2009, 15,
10330–10334; (f) Jahn, U.; Rudakov, D.; Jones, P. G. Tetrahedron 2012, 68, 1521–
1539.
6. Bromolactamization of unsaturated amide: (a) Biloski, A. J.; Wood, R. D.;
Ganem, B. J. Am. Chem. Soc. 1982, 104, 3235–3236; (b) Rajendra, G.; Miller, M. J.
J. Org. Chem. 1987, 52, 4471–4477; (c) Balko, T. W.; Brinkmeyer, R. S.; Terando,
N. H. Tetrahedron Lett. 1989, 30, 2045–2048; (d) Boeckman, R. K.; Connell, B. T. J.
Am. Chem. Soc. 1995, 117, 12368–12369; (e) Lei, A.; Lu, X.; Liu, G. Tetrahedron
Lett. 2004, 45, 1785–1788; (f) Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler,
S. R. Organometallics 2004, 23, 5618–5621; (g) Yeung, Y.-Y.; Corey, E. J.
Tetrahedron Lett. 2007, 48, 7567–7570.
7. Dibromides 7b and 7d were generated by an SN2 reaction of bromonium with
magnesium bromide, which was consumed during the PhI(OAc)2-mediated
reaction by oxidation to 8. This might be the reason for suppressed generation
of 7b and 7d in oxidative bromolactamization.
Scheme 5. A one-pot synthesis of cyclic amine 11 using Grignard reagent 1 and
imine 10.
product 4d (56%). Oxidative bromolactamization with PhI(OAc)2
suppressed the formation of dibrominated product 7b and 7d.7
The putative reaction pathway is shown in Scheme 4. Reaction
of the Grignard reagent with isocyanate gave magnesium amide
3a, and subsequent treatment with PhI(OAc)2 generated bromoiod-
inane 8, which acted as a Br+ equivalent to give bromonium 9a,8,9
and finally nucleophilic opening gave bromolactam 4a.10,11 The use
of Grignard reagent 1d led to an intramolecular SN2-type opening
reaction of amide with bromonium of intermediate 9d, which pro-
ceeded at the positively charged benzyl position and resulted in
the formation of trans-6-endo cyclized product 4d, suggesting a
Br+ reaction instead of a radical reaction.12 The characteristic
feature of this reaction is that both alkyl group and bromide of
Grignard reagent were incorporated in the reaction product.
This one-pot process was also applicable to the synthesis of cyc-
lic amine by the reaction of imine in place of isocyanate (Scheme
5). The reaction of Grignard reagent 1a, 1c with N-tosylimine
10a, 10b followed by PhI(OAc)2 oxidation gave cyclic sulfonamide
11a, 11b in 68% and 52% yield, respectively.
8.
A similar mechanism was suggested in LiBr and PhI(OAc)2-mediated
bromolactonization of unsaturated carboxylic acids. (a) Braddock, D. C.;
Cansell, G.; Hermitage, S. A. Synlett 2004, 461–464; (b) Braddock, D. C.;
Cansell, G.; Hermitage, S. A.; White, J. P. Chem. Commun. 2006, 1442–1444; The
formation of
a
bromonium intermediate was suggested in the
bromocyclization of homoallylic sulfonamides with the Bu4NBr–PhI(OAc)2
system: (c) Fan, R.; Wen, F.; Qin, L.; Pu, D.; Wang, B. Tetrahedron Lett. 2007, 48,
7444–7447.
In conclusion,
achieved by a tandem reaction of
a
one-pot synthesis of bromolactams was
-alkenylmagnesium bromide
x
9. Oxidation of 3a with peroxide (Table 1, entries 6–11) would generate
with C@N double bond–oxidative bromolactamization. The
methodology could be applied to the synthesis of brominated
cyclic amine using imines as electrophiles.
hypobromous acid or its anhydride as Br+ sources.
10. Hypervalent iodine-mediated cyclization reactions of
x-alkenamides: (a)
Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 625–
628; (b) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong, Y.-L.; Sugita, K.; Zou, N.
Angew. Chem., Int. Ed. 2001, 40, 202–206; (c) Nicolaou, K. C.; Baran, P. S.; Zhong,
Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002,
124, 2233–2244; (d) Serna, S.; Tellitu, I.; Domínguez, E.; Moreno, I.; SanMartín,
R. Tetrahedron Lett. 2003, 44, 3483–3486; (e) Janza, B.; Studer, A. J. Org. Chem.
2005, 70, 6991–6994.
Acknowledgments
This research was partially supported by JSPS KAKENHI Grant
Numbers 23790029, 24590035.
11. According to Ref. 10c, cyclization of 5a with IBX did not proceed at all.
Treatment of 5a with PhI(OAc)2 was also reported to result in no reaction.
Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690–7691.
12. Another possible mechanism of cyclization of an amidyl radical generated by
an oxidation of magnesium amide was unlikely because 5-exo-cyclized
product, which should be generated by cyclization of amidyl radical
according to the Baldwin rule, was not obtained at all in the reaction of 1d.
Supplementary data
Supplementary data (experimental details and characterization
data of new compounds) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
06.002.