Cyclic 1-(Arylamino)carboxylates via Mild Diastereospecific Jocic-Type Reaction with 2,2,2-Trichloromethyl Carbinols and Anilines

Article abstract of DOI:10.1055/s-0036-1588330

A mild, practical Jocic-type rearrangement for the synthesis of cyclic 1-(arylamino) carboxylates from readily available 2,2,2-trichloromethyl carbinols and anilines is described. The method demonstrates good scope, with a large variety of anilines providing direct access to several novel cyclic 1-(arylamino) carboxylates. The reaction is robust and has been shown to provide comparable results on kilogram scale. The reaction is diastereospecific, leading to the formation of a single diastereomer when utilizing stereodefined 2,2,2-trichloromethyl carbinol cores.

Full text of DOI:10.1055/s-0036-1588330

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
R. Lira et al.
Letter
Synlett
Cyclic 1-(Arylamino)carboxylates via Mild Diastereospecific Jocic-
Type Reaction with 2,2,2-Trichloromethyl Carbinols and Anilines
R2
O
R1
Ricardo Lira*
Kevin E. Henegar
Neil Baldwin1
Kevin Ogilvie
R1
Cl3C
OH
H
Cs2CO3 (3.5 equiv)
N
N
OMe
R2
+
MeOH, 0 to 5 °C
17 examples
(1 equiv)
(3 equiv)
Pfizer Global Research and Development, Groton Laboratories
Eastern Point Road, Groton, CT 06340, USA
ricardo.lira@pfizer.com
Received: 29.07.2016
Accepted after revision: 19.09.2016
Published online: 06.10.2016
O
O
H
O
H
H
N
N
N
OMe
NH
OMe
DOI: 10.1055/s-0036-1588330; Art ID: st-2016-r0493-l
Br
OH
F
N
N
Abstract A mild, practical Jocic-type rearrangement for the synthesis
of cyclic 1-(arylamino) carboxylates from readily available 2,2,2-tri-
chloromethyl carbinols and anilines is described. The method demon-
strates good scope, with a large variety of anilines providing direct ac-
cess to several novel cyclic 1-(arylamino) carboxylates. The reaction is
robust and has been shown to provide comparable results on kilogram
scale. The reaction is diastereospecific, leading to the formation of a
single diastereomer when utilizing stereodefined 2,2,2-trichloromethyl
carbinol cores.
Boc
Cbz
1, B-secretase ligand
precursor
2, cathepsin K inhibitor
3, carfentanil
precursor
precursor
Figure 1 Examples of cyclic 1-(arylamino) carboxylate motifs in pre-
cursors of compounds with pharmaceutical value
of β-secretase ligand precursor 1.2b,9 Formation of product 1
has been proposed to proceed via a Jocic-type rearrange-
ment involving a transient gem-dichlorooxirane, followed
Key words Jocic rearrangement, 2,2,2-trichloromethyl carbinols, cy-
clic 1-(arylamino) carboxylates, diastereospecific, anilines
previous work
The cyclic 1-(arylamino) carboxylate functionality is an
important moiety found in a variety of precursor com-
pounds with pharmaceutical value (Figure 1).2 Among the
most common strategies to access such structures are the
Strecker reaction3 and the metal-catalyzed N-arylation of
hindered α-amino carbonyl precursors (Scheme 1).4 Most
recently, Read de Alaniz reported a procedure involving a
copper-catalyzed radical addition to aryl nitroso species
from α-bromo esters.5,6 However, despite the mild condi-
tions of this protocol, which allows a variety of functional
groups, the cost and safety associated with handling and
isolating the highly reactive nitroso species as well as the
use of SmI2 limits its practicality for large-scale applica-
tions.
a. Strecker reaction
O
NH2
O
H
N
CN
OR
+
b. N-arylation
O
O
Br
H
N
H2N
OMe
OMe
+
metal
c. electrophylic amination
O
O
O
N
H
Br
X
N
X
Cu*
+
SmI2
X = OR, NHR
this work
X = OR, NHR
As part of an internal drug-discovery effort, we recently
disclosed an example of a chemical transformation to ac-
cess the key methyl 2-alkyl-2-(arylamino) acetate interme-
diate 1 from the readily accessible 2,2,2-trichloromethyl
carbinol 4.2b,7,8 The reaction conditions were mild and re-
producible on large scale providing more than 1 kilogram
d. aniline Jocic-type reaction with trichloromethyl carbinols
O
NHR
Cl
Cl
Cl
H
N
HO
OR
+
Scheme 1 Common strategies to access cyclic 1-(arylamino) carboxyl-
ates and this work
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
R. Lira et al.
Letter
Synlett
by an anti diastereospecific nucleophilic attack at the no-
chloride-bearing oxirane quaternary center by the aniline
nitrogen leading to an acylchloride species which is then
trapped with methanol.2a,b,10
Table 1 Organic and Inorganic Base Screen with Substrate 4 and 3-
Fluoroaniline; Crude HPLC Ratios
O
O
F
H
N
MeO
OMe
OMe
Herein we demonstrate the substrate scope of this pro-
cedure for the preparation of cyclic 1-(arylamino) carboxyl-
ates utilizing readily available 2,2,2-trichloromethyl carbi-
nols and a variety anilines with a focus on piperidine-2,2,2-
trimethyl carbinol core 4.2a,b,10
We initiated reaction optimization by evaluating a di-
verse set of both organic (amines) and inorganic bases. The
purpose was to go beyond the ‘preferred’ bases previously
disclosed for related transformations.2a,11 The effectiveness
of each base was assessed by measuring the relative ratios
of starting material 4 to product 1 along with known side
products methoxy-methyl ester 5 and amide 6 (Table 1).
Pyridine-like amines (entries 1–3), as well as both cyclic al-
kyl (entries 4–6) and acyclic alkyl-amines (entries 7 and 8)
proved to be ineffective and led to only trace amounts of
desired product formation (1).
More strongly basic cyclic amines, such as DBU (entry
10), DBN ( entry 9), and TBD (entry 12) proved superior
with complete starting material consumption and varying
degrees of side-product formation observed. Ultimately,
DBU was determined to be the most effective organic base
for the desired transformation.
Subsequently, a small set of anionic bases was screened,
as shown in Table 1 (entries 13–24). Unexpectedly, cesium
carbonate was found to be the base with the best reaction
profile of all the bases screened, including the organic bas-
es, leading to complete starting material consumption and
minimal side-product formation. In contrast, stronger bases
such as lithium hydroxide, sodium hydroxide, potassium
hydroxide, sodium methoxide, and potassium tert-butoxide
(entries 19–24) led to the formation of significant amounts
of side product 5.
With cesium carbonate identified as the optimum base,
the scope of the reaction was evaluated with various ani-
lines and the 2,2,2-trichlomethyl carbinol 4 (Table 2). In
general, anilines with a single 2-, 3-, or 4-aryl substituent
performed well under the optimized reaction conditions,
leading to 64–79% isolated yields of the desired products
(entries 1–5, 9). A slight decrease in yield was seen with 2,
4-difluoroaniline (entry 6, 58%), electron-rich 4-dimeth-
ylaniline (entry 8, 31%) and 1-methyl-5 amino indole (entry
13, 25%). Interestingly, the bulky 2-tert-butyl aniline also
provided the desired product, albeit in a modest 30% isolat-
ed yield (entry 10). N-Methyl-N-phenylaniline also led to
lower yield (entry 11, 31%), while the N,N-biphenyl aniline
in entry 12, resulted in recovered starting material 4 and no
detectable product. All products shown in Table 2 were iso-
lated as a single diastereomer, further demonstrating the
utility of the transformation.2b,12
F
Cl3C
OH
NH2
N
N
(3 equiv)
1
5
Cbz
Cbz
N
base (3.5 equiv)
MeOH, 0 to 5 °C
Cbz
O
F
F
H
4 (1 equiv)
N
N
H
N
6
Cbz
Entry Base
Starting
Product Side
1 product 5 product 6
Side
material 4
1
2
pyridine
>98
>96
>96
94
94
95
100
95
0
0
0
0
0
0
0
lutidine
3
collidine
N-methylmorpholine
N-methylpiperidine
N-methylpyrrolidine
Et3N
0
0
0
4
6
0
0
5
4
2
0
6
5
0
0
7
0
0
0
8
DIPEA
5
0
0
9
DBNa
75
77
81
82
8
16
9
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
DBUb
0
3
tetramethyl guanidine
TBDc
7
9
3
0
15
0
3
NaOAc
92
88
100
83
7
0
NaHCO3
Ag2CO3
7
5
0
0
0
0
Na2CO3
5
0
12
5
K2CO3
80
86
75
78
41
74
11
9
8
Cs2CO3
0
11
24
17
22
25
19
91
2
LiOH
0
0
NaOMe
0
0
KOt-BU
0
0
NaOH
0
<1
0
KOH
70
0
TBAHd
0
a DBN = 1,5-diazabicyclo[4.3.0]non-5-ene.
b DBU = 1,8-diazabicyclo]5.4.0]undec-7-ene.
c TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene.
d TBAH = 1.5 M solution of tetrabutylammonium hydroxide in water.
In order to explore the scope of the reaction with other
carbinol substrates, the symmetric cyclohexyl carbinol sub-
strate 7 was evaluated with both electron-deficient and
electron-rich anilines. Treatment of carbinol 7 under the
optimized conditions, with electron-deficient 4-trifluoro-
methyl- and 3-nitroaniline provided the desired products 8
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
R. Lira et al.
Letter
Synlett
Table 2 Scope of Anilines under the Optimized Conditions
leading to the formation of a single cyclic 1-(arylamino)
carboxylate diastereomer when starting with stereodefined
2,2,2-trichloromethyl carbinols.
R2
R1
R2
O
R1
Cl3C
OH
NH
N
OMe
O
(3 equiv)
HO
CCl3
CbzN
Me
optimized
conditions
CbzN
Me
O
N
OMe
Cs2CO3 (3.5 equiv)
MeOH, 0 to 5 °C
Cbz
N
NH
Cl
3-fluoro-
aniline
Cl
Cbz
N
4 (1 equiv)
1
NH2
Cbz
Ph
Entry
Compd
R1
R2
Yield (%)a,b
12
13
F
1
2
1
3-fluoro
2-fluoro
2-chloro
4-chloro
3-cyano
2,4-difluoro
3,4-dimethyl
4-N,N-dimethyl
2-phenyl
2-tert-butyl
H
H
76
76
79
74
64
58
73
31
76
30
31
0
Scheme 3 Support of diastereospecificity with epimer 12
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
H
3
In conclusion, a mild and practical method for the syn-
thesis of cyclic 1-(arylamino) carboxylates is described.14
The method uses readily available 2,2,2-trichloromethyl
carbinols and proceeds well with a large variety of aniline
and aniline-like partners. The robustness of the reaction
has been previously demonstrated in the preparation of >1
kilogram of intermediate 1. Furthermore, the reaction was
found to be diastereospecific, leading to the formation of a
single diastereomer when utilizing stereodefined 2,2,2-tri-
chloromethyl carbinol templates. Thus, based on the above
features, we anticipate this transformation to be of great
utility.
4
5
6
7
8
1g
1h
1i
9
10
11
12
13
1j
Me
Ph
1k
1l
H
1-methyl-1H-indol-5-amine
25
a Isolated yield.
b Products isolated as a single diastereomer.
Acknowledgment
The authors acknowledge Yvette Fobian, Anabella Villalobos, Chris
Helal, Mike Brodney, and Brian O’Neill for supporting this research.
and 9 in 75% and 63% yield, respectively (Scheme 2). The
use of the electron-rich 4-OMe-aniline led to desired prod-
uct 10, but in a reduced yield (41%), due to the competitive
formation of the amide side product 11 (35%).
Supporting Information
Supporting information for this article is available online at
O
H
N
http://dx.doi.org/10.1055/s-0036-1588330.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
R
OMe
Cl3C
OH
conditions
from Table 2
aniline
References and Notes
8, R = 4-CF3, 75%
7
9, R = 3-NO2, 63%
10, R = 4-OMe, 41%,
(1) New Address: N. Baldwin, Ingredion Incorporation, 6400 S
Archer Rd, Bedford Park, Illinois 60501, USA.
O
H
(2) (a) Lee, C.-W.; Lira, R.; Dutra, J.; Ogilvie, K.; O’Neill, B. T.;
Brodney, M.; Helal, C.; Young, J.; Lachapelle, E.; Sakya, S.; Murra,
J. C. J. Org. Chem. 2013, 78, 2661. (b) Henegar, K. E.; Lira, R.; Kim,
H.; Gonzalez-Hernandez, J. Org. Process Res. Dev. 2013, 17, 985.
(c) Romero, D. L.; Olmsted, R. A.; Poel, T. J.; Morge, R. A.; Biles,
C.; Keiser, B. J.; Kopta, L. A.; Friis, J. M.; Hosley, J. D.; Stefanski, K.
J.; Wishka, D. G.; Evans, D. B.; Morris, J.; Stehle, R. G.; Sharma, S.
K.; Yagi, Y.; Voorman, R. L.; Adams, W. J.; Tarpley, W. G.;
Thomas, R. C. J. Med. Chem. 1996, 39, 3769. (d) Bladh, H.;
Dahmen, J.; Hansson, T.; Henriksson, K.; Lepisto, M.; Nilsson, S.
WO 2007046747, 2007. (e) Shinozuka, T.; Shimada, K.; Matsui,
S.; Yamane, T.; Ama, M.; Fukuda, T.; Taki, M.; Takeda, Y.; Otsuka,
E.; Yamato, M.; Mochizuki, S.-i.; Ohhata, K.; Naito, S. Bioorg.
Med. Chem. 2006, 14, 6789.
R
N
N
H
R
11, R = 4-OMe, 35%
Scheme 2 Cyclohexyl-derived analogues
To further support the diastereospecific nature of this
transformation, 4-epi-carbinol 12 was subjected to the op-
timized reaction conditions (Scheme 3). From the reaction,
epimer 13 emerged as the sole diastereomer in 56% isolated
yield, though in lower yield than that obtained with carbi-
nol 4 (1, Table 1, 76%).13 The nucleophilic attack of the ani-
line from the congested bottom side of the ring highlights
the high degree of stereofidelity for the transformation
(3) (a) Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27.
(b) Strecker, A. Justus Liebigs Ann. Chem. 1854, 91, 349. (c) Wang,
J.; Liu, X.; Feng, X. Chem. Rev. 2011, 111, 6947.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
R. Lira et al.
Letter
Synlett
(4) (a) Ruiz-Castillo, P.; Blackmond, D. G.; Buchwald, S. L. J. Am.
Chem. Soc. 2015, 137, 3085. (b) Park, N. H.; Vinogradova, E. V.;
Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2015, 54, 8259.
(5) Fisher, D. J.; Burnett, G. L.; Velasco, R.; Read de Alaniz, J. J. Am.
Chem. Soc. 2015, 137, 11614.
(6) For other selected methods to access cyclic 1-(arylamino) car-
boxylates, see: (a) Mailig, M.; Rucker, R. P.; Lalic, G. Chem.
Commun. 2015, 51, 11048. (b) Berman, A. M.; Johnson, J. S. J. Am.
Chem. Soc. 2004, 126, 5680. (c) del Amo, V.; Dubbaka, S. R.;
Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 7838.
(d) Barker, T. J.; Jarvo, E. R. J. Am. Chem. Soc. 2009, 131, 15598.
(7) For recent methods to access 2,2,2-trichloromethyl carbinols,
see: (a) Henegar, K. E.; Lira, R. J. Org. Chem. 2012, 77, 2999.
(b) Gupta, J. K.; Li, Z.; Snowden, T. S. J. Org. Chem. 2012, 77, 4854.
(c) Jensen, A. B.; Lindhardt, A. T. J. Org. Chem. 2014, 79, 1174.
(d) Perryman, M. S.; Harris, M. E.; Foster, J. L.; Joshi, A.; Clarkson,
G. J.; Fox, D. J. Chem. Commun. 2013, 49, 10022.
(8) For previous selected examples of nucleophilic addition of
amines to 2,2,2-trichloromethyl carbinols, see: (a) Reeve, W.;
Fine, L. W. J. Org. Chem. 1964, 29, 1148. (b) Dominguez, C.;
Ezquerra, J.; Baker, S. R.; Borrelly, S.; Prieto, L.; Espada, M.;
Pedregal, C. Tetrahedron Lett. 1998, 39, 9305. (c) Tanaka, N.;
Tamai, T.; Mukaiyama, H.; Hirabayashi, A.; Muranaka, H.;
Akahane, S.; Miyata, H.; Akahane, M. J. Med. Chem. 2001, 44,
1436. (d) Butcher, K. J.; Hurst, J. Tetrahedron Lett. 2009, 50, 2497.
(e) Rohman, M. R.; Myrboh, B. Tetrahedron Lett. 2010, 51, 4772.
(9) Intermediate 1 was successfully telescoped to the next steps in
the sequence without the need of purification, see ref. 2b.
(10) (a) Jocic, Z. Zh. Russ. Fiz. Khim. Ova. 1897, 29, 97. (b) For recent
synthetic applications involving gem-dichloroepoxides see:
Snowden, T. S. ARKIVOC 2012, (ii), 24.
(11) DBU and NaOH are the most widely used bases for similar
transformations. For selected examples, see: (a) Corey, E. J.;
Link, J. O. J. Am. Chem. Soc. 1992, 114, 1906. (b) Scaffidi, A.;
Skelton, B. W.; Stick, R. V.; White, A. H. Aust. J. Chem. 2006, 59,
426. (c) Dominguez, C.; Ezquerra, J.; Baker, S. R.; Borrelly, S.;
Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron Lett. 1998, 39,
9305. (d) Liu, G.; Romo, D. Org. Lett. 2009, 11, 1143.
(e) Tennyson, R. L.; Cortez, G. S.; Galicia, H. J.; Kreiman, C. R.;
Thompson, C. M.; Romo, D. Org. Lett. 2002, 4, 533. (f) Morimoto,
H.; Wiedemann, S. H.; Yamaguchi, A.; Harada, S.; Chen, Z.;
Matsunaga, S.; Shibasaki, M. Angew. Chem. Int. Ed. 2006, 45,
3146.
(12) For all products, a single diastereomer was detected by HPLC.
Stereochemistry was assigned by analogy to product 2.[2a,b]
(13) The lower yield is attributed to the competing formation of side
product methoxy methyl ester of the type of 5 (Table 1). Side
product was detected by mass (UPLC/MS) and was not iso-
lated/characterized.
(14) General Experimental Procedure
Preparation of (2S,4R)-1-Benzyl 4-Methyl 4-(3-Cyanophenyl-
amino)-2-methylpiperidine-1,4-dicarboxylate (1d, Table 2,
Entry 5) from (2S,4S)-4-Hydroxy-2-methyl-4-(trichloro-
methyl)piperidine-1-carboxylate (4)
To a 20 mL vial equipped with a stir bar was charged with
(2S,4S)-benzyl 4-hydroxy-2-methyl-4-(trichloromethyl)piperi-
dine-1-carboxylate (4, 367 mg, 1 mmol), MeOH (2 mL), and 3-
aminobenzonitrile (354 mg, 3 mmol). The resulting homoge-
neous reaction mixture was placed in a precooled plate at 0 °C
and was stirred for 10 min. To the cooled reaction mixture was
added Cs2CO3 (1.2 g, 3.5 mmol) in two portions over a period of
about 10 min. The mixture was then warmed to 5 °C and stirred
for 42 h. The reaction mixture was removed from the cold bath
and was concentrated under reduced pressure in the rotavap to
a gum. To the crude reaction mixture was then added MTBE (10
mL) and was transferred to an extraction funnel with MTBE (10
mL). The cloudy solution was washed with 0.5 N HCl (2 × 5 mL)
and brine (5 mL). The organic layer was then dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pres-
sure in the rotovap. The resulting crude material was purified
twice by silica gel flash chromatography (isco CombiFlash puri-
fication system, 24 g HP silica column, 0–60% EtOAc–heptane)
and provided compound 1d as a gum in 64% yield (268 mg).
1H NMR (400 MHz, CDCl3): δ = 7.31–7.37 (m, 5 H), 7.17–7.21 (m,
1 H), 7.01–7.03 (m, 1 H), 6.76–6.77 (m, 1 H), 6.73 (ddd, J = 8.0,
2.4, 0.8 Hz, 1 H), 5.14 (s, 2 H), 4.34–4.39 (m, 1 H), 4.21 (s, 1 H),
4.07 (ddd, J = 14.0, 5.6, 2.4 Hz, 1 H), 3.70 (s, 3 H), 3.27 (ddd, J =
14.4, 12.4, 4.0 Hz, 1 H), 2.60–2.64 (m, 1 H), 2.19 (ddd, J = 14.0,
5.6, 1.2 Hz, 1 H), 2.07 (dd, J = 13.6, 6.0 Hz, 1 H), 1.70 (ddd, J =
13.6, 12.4, 5.6 Hz, 1 H), 1.15 (d, J = 6.8 Hz, 3 H). 13C (100 MHz,
CDCl3): δ = 174.5, 155.1, 145.4, 136.6, 129.9, 128.4, 128.0, 127.8,
122.3, 119.2, 119.0, 117.6, 112.9, 67.1, 57.5, 52.6, 45.6, 38.6,
36.1, 33.1, 17.7. ESI-HRMS: m/z calcd for C23H25N3O4 [M + H]+:
408.1918; found: 408.1918.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D