Preparation of rearranged allylic isocyanates from the reaction of allylic alcohols with 1-Cyano-4-dimethylaminopyridinium bromide

Article abstract of DOI:10.1055/s-0037-1610659

A shorter and less costly alternative to Ichikawa's [1,3]-Transposition protocol for cyanates to isocyanates is described.

Full text of DOI:10.1055/s-0037-1610659

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–E
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D. Baidilov et al.
PSP
Synthesis
Preparation of Rearranged Allylic Isocyanates from the Reaction
of Allylic Alcohols with 1-Cyano-4-dimethylaminopyridinium
Bromide
R1
Daler Baidilov
Mariia Makarova
Lukas Rycek
R1
R2
BrCN, DMAP
R2
OH
R3
CH2Cl2, 0 °C to rt
one synthetic operation
N
R3
C
Tomas Hudlicky*
0
0
0
0-0
0
0
3-
3
2
3
9-6
8
1
5
O
9 examples
up to 74% yield
Department of Chemistry and Centre for Biotechnology,
Brock University, 1812 Sir Isaac Brock Way, St. Catha-
rines, ON L2S 3A1, Canada
thudlicky@brocku.ca
Received: 14.07.2018
Accepted after revision: 05.09.2018
Published online: 11.10.2018
arranged to allylic isocyanate 3. Following this observation,
several attempts have been made to make this reaction use-
ful as a synthetic tool,2 the most successful of which is the
work by Ichikawa3 in 1991. He reported an efficient method
for the synthesis of allylic cyanate 6 by dehydration of allylic
carbamate 5, which, after [3,3]-sigmatropic rearrangement,
provided the desired allylic isocyanate 7 (Scheme 1, eq. 2).
Later in 1994, Ichikawa demonstrated that cyanate-to-iso-
cyanate rearrangement is a truly concerted [3,3]-sigma-
tropic process involving highly selective [1,3]-chirality
transfer to the newly-formed nitrogen-bearing center, as
was postulated earlier by Holms.3e
DOI: 10.1055/s-0037-1610659; Art ID: ss-2018-n0474-psp
Abstract A shorter and less costly alternative to Ichikawa’s [1,3]-trans-
position protocol for cyanates to isocyanates is described.
Key words sigmatropic rearrangement, [1,3]-transposition, allylic
alcohol, methodology, total synthesis
[3,3]-Sigmatropic rearrangement of allylic cyanate to
allylic isocyanate was first reported by Holms1 in 1970
(Scheme 1, eq. 1). Chelotropic rupture of thiatriazole 1 pro-
vided allylic cyanate intermediate 2, which immediately re-
In this paper, we wish to report our observations on the
reactions of allylic alcohols with in situ formed 1-cyano-4-
dimethylaminopyridinium bromide (CAP): a convenient
source of electrophilic cyanide,4 Scheme 2.
(Eq. 1)
R1
NMe2
N
O
R2
OH
O
N
R1
– N2
– S
R2
R3
N
S
R3
NCO
N
N
iPr2NEt
CH2Cl2, 0 °C to rt
1
2
3
NCO
Br
N
(Eq. 2)
O
O
1)
Cl3C
CH2Cl2, rt
N
CAP
O
NH2
OH
O
NCO
Scheme 2 Direct approach to rearranged allylic isocyanates by the
Tf2O, iPr2NEt
reaction of allylic alcohols with CAP
2) K2CO3
aq MeOH, rt
CH2Cl2, –78 °C
4
5
6
4-(Dimethylamino)pyridine readily activates cyanogen
bromide towards nucleophilic attack by forming CAP
(Scheme 2). This reagent has been reported to produce cya-
nate derivatives of enzymes and various imidazole deriva-
tives4 but, surprisingly, this electrophilic activation of cy-
anogen bromide has not been exploited further in synthetic
organic chemistry.5 We felt that the conversion of cyanogen
bromide into CAP should also serve as a convenient cyanat-
NCO
7
Scheme 1 [3,3]-Sigmatropic rearrangement of allylic cyanates to
allylic isocyanates
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

B
D. Baidilov et al.
PSP
Synthesis
ing agent to prepare allylic cyanates from allylic alcohols di-
rectly, thus allowing rapid access to rearranged allylic iso-
cyanates.
NMe2
NMe2
N
NMe2
N
R
HO
R
O
N
N
O
R
Treatment of 4-(dimethylamino)pyridine solution in di-
chloromethane with cyanogen bromide immediately pro-
vided a pale-yellow precipitate of CAP. Sequential addition
of diisopropylethylamine and allylic alcohol furnished the
rearranged allylic isocyanate in less than 30 minutes at 0 °C.
The resulting isocyanates were characterized as stable
ureas, produced by subsequent trapping with pyrrolidine.
The generality of this approach was examined on a number
of model substrates, as shown in Table 1.6–11 The procedure
works best for primary allylic alcohols. Propargyl alcohol
15a (Table 1, entry 8) and sterically congested (R)-carvone
derivative 16a (entry 9) failed to react. We anticipate that
the low yields for the transformation described herein can
be attributed to electrophilicity of C-2 in CAP (DMAP num-
bering, Scheme 3). Unfortunately, no side product could be
isolated from the reaction mixture. Finally, synthetic utility
of this methodology in natural product synthesis was
demonstrated on the preparation of Fukuyama’s advanced
H
Br
:B
N
Scheme 3 Rationale for the low yields of [3,3]-sigmatropic rearrange-
ment mediated by CAP and suggested possible side product
intermediate 18 used in his total synthesis of tetrodotoxin
(entries 10 and 11). Both geometric isomers of 17 were
converted into Fukuyama’s carbamate 18 in one synthetic
operation as opposed to two operations previously report-
ed.11 Furthermore, none of the other diastereomeric prod-
uct was observed during the course of this transformation,
highlighting the stereoselectivity of the sigmatropic rear-
rangement approach to install the nitrogen functionality.
In summary, a shorter and less costly alternative to
Ichikawa’s [1,3]-transposition protocol for cyanates to iso-
cyanates is described.
Table 1 Conversion of Allylic Alcohols into Rearranged Allylic Ureasa
Entry
Substrate [Ref]
Product [Ref]b
Yield (%)c
O
OH
N
N
H
1
72
8a
8b3a
OH
H
N
N
2
3
46
52
O
N
9a6
9b3a
O
OH
N
H
10a
10b3a
O
OH
N
N
4
5
44
37
H
11a7
11b
OH
O
N
N
H
12b2,3a
12a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

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D. Baidilov et al.
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Synthesis
Table 1 (continued)
Entry
Substrate [Ref]
Product [Ref]b
Yield (%)c
OH
H
N
N
6
7
74
35
O
13a8
13b
H
OH
N
N
O
14a8
14b
e
O
OH
HN
N
8
9
–
–
15a9
15b
OH
e
O
N
N
H
16a10
16b
O
O
O
O
O
O
10d
39
O
O
NHBoc
OH
17a11a
1811
O
O
O
O
O
O
O
11d
35
O
NHBoc
HO
17b11b
1811
a Reactions were performed according to the typical procedure reported for 8b.
b Isocyanates were characterized as stable ureas, which were produced by reaction with pyrrolidine.
c Isolated yields after chromatographic purification.
d Intermediate isocyanate was trapped with LiOt-Bu (1.0 M in THF).
e Not formed.
1H NMR and 13C NMR spectra were recorded on a 300 MHz Bruker
spectrometer. Chemical shifts for 1H NMR are reported in parts per
million (ppm) with reference to non-deuterated residual CHCl3 sol-
vent peak at 7.26 ppm. Data for proton spectra are reported as of fol-
lowing format: chemical shift (multiplicity, standard abbreviations),
coupling constants (Hz), integration. Chemical shifts for 13C NMR
were reported in ppm relative to the central line of a triplet at 77.16
ppm for CDCl3. Optical rotations were measured on a Mandel Rudolph
Research Analytical Automatic Polarimeter at 589 nm with a cell
length of 50 mm. IR spectra were recorded on a Bruker ATR Fourier
Transform Infrared Spectrophotometer and were reported in wave-
numbers (cm–1). Mass spectra and high-resolution mass spectra were
obtained by the analytical division at Brock University. Melting points
were determined on a Hoover Unimelt apparatus and are uncorrect-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

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ed. Analytical TLC was performed on EMD Silica Gel 60 Å 250 μm
plates with F-254 indicator, while column chromatography was per-
formed using Silicycle SiliaFlash P60 (230–400 mesh).
13C NMR (75 MHz, CDCl3): δ = 155.9, 142.0, 138.8, 128.7, 127.4, 127.3,
115.3, 56.1, 45.6, 25.6.
HRMS (EI+): m/z calcd for C14H18N2O: 230.1419; found: 230.1413.
CH2Cl2 was freshly distilled from CaH2 prior to use. Commercial n-
hexane was re-distilled prior to column chromatography to minimize
the grease content. i-Pr2NEt (Hünig’s base) was distilled from KOH
and stored over KOH pellets. All other chemicals/solvents were pur-
chased from either Sigma-Aldrich or Oakwood Chemicals and used as
received. All reactions were conducted under an argon atmosphere
using standard Schlenk techniques.
N-[1-(Naphthalen-2-yl)allyl]pyrrolidine-1-carboxamide (11b)
Yield: 93 mg (44%), starting from 11a (138 mg, 0.75 mmol); white
solid; mp 131–132 (EtOAc/n-hexane).
IR (neat): 3319, 2970, 2870, 1612, 1517, 1378, 1206 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.87–7.74 (m, 4 H), 7.52–7.40 (m, 3 H),
6.16 (ddd, J = 17.4, 10.0, 5.3 Hz, 1 H), 5.84–5.66 (m, 1 H), 5.35–5.17
(m, 2 H), 4.54 (d, J = 8.0 Hz, 1 H), 3.51–3.24 (m, 4 H), 1.99–1.82 (m, 4
H).
N-(3,7-Dimethylocta-1,6-dien-3-yl)pyrrolidine-1-carboxamide
(8b);3a
13C NMR (75 MHz, CDCl3): δ = 155.9, 139.4, 138.7, 133.4, 132.8, 128.4,
Typical Procedure
128.0, 127.6, 126.2, 125.9, 125.8, 125.7, 115.6, 56.1, 45.6, 25.6.
To a stirred solution of DMAP (275 mg, 2.25 mmol) in CH2Cl2 (4 mL)
was added BrCN (3.0 M in CH2Cl2, 0.75 mL, 2.25 mmol) dropwise at 0
°C. A pale-yellow precipitate of 1-cyano-4-dimethylaminopyridinium
bromide was immediately formed and the mixture was allowed to stir
for another 5 min whereupon i-Pr2NEt (0.2 mL, 1.13 mmol) followed
by geraniol (8a; 121 mg, 0.75 mmol) in CH2Cl2 (0.5 mL) were added at
at 0 °C. The resulting reaction mixture was warmed up to r.t. and
stirred until the full consumption of the starting material (ca. 20
min). The mixture was cooled to 0 °C and pyrrolidine (0.43 mL, 5.25
mmol) was slowly added. Cooling bath was removed and the mixture
was stirred for another 1 h at r.t. Then, volatiles were removed under
reduced pressure and the residue was purified by silica gel column
chromatography (EtOAc/n-hexane 1:1) to furnish urea 8b as a color-
less oil; yield: 187 mg (72%).
HRMS (EI+): m/z calcd for C18H20N2O: 280.1576; found: 280.1572.
N-(Cyclohex-2-en-1-yl)pyrrolidine-1-carboxamide (12b)2,3a
Yield: 54 mg (37%), starting from 12a (74 mg, 0.75 mmol); white sol-
id; mp 88–91 °C (EtOAc/n-hexane).
IR (neat): 3297, 2930, 2849, 1612, 1514, 1294, 1192, 699 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.86–5.74 (m, 1 H), 5.70–5.56 (m, 1 H),
4.45–4.30 (m, 1 H), 4.20–4.03 (m, 1 H), 3.31 (m, 4 H), 2.04–1.93 (m, 2
H), 1.93–1.82 (m, 5 H), 1.69–1.58 (m, 2 H), 1.58–1.45 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 156.3, 130.3, 129.3, 45.6, 45.5, 30.5,
25.7, 25.1, 19.9.
HRMS (EI+): m/z calcd for C11H18N2O: 194.1419; found: 194.1417.
IR (neat): 3340, 2967, 2927, 2869, 1637, 1523, 1450, 1374, 1195, 911,
765 cm–1
.
Anal. Calcd for C11H18N2O: C, 68.01; H, 9.34. Found: C, 67.98; H; 9.19.
1H NMR (300 MHz, CDCl3): δ = 5.97 (dd, J = 17.3, 11.0 Hz, 1 H), 5.20–
4.96 (m, 3 H), 4.21 (s, 1 H), 3.36–3.19 (m, 4 H), 2.00–1.90 (m, 2 H),
1.90–1.83 (m, 4 H), 1.79–1.67 (m, 2 H), 1.65 (s, 3 H), 1.57 (s, 3 H), 1.44
(s, 3 H).
N-(1-Vinylcyclohexyl)pyrrolidine-1-carboxamide (13b)
Yield: 123 mg (74%), starting from 13a (95 mg, 0.75 mmol); white
solid; mp 101–102 °C (EtOAc/n-hexane).
IR (neat): 3313, 2971, 2851, 1618, 1524, 1377, 910 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 156.0, 144.8, 131.7, 124.5, 111.7, 56.7,
1H NMR (300 MHz, CDCl3): δ = 6.07 (dd, J = 17.5, 10.7 Hz, 1 H), 5.10
(dd, J = 17.5, 1.1 Hz, 1 H), 5.04 (dd, J = 10.7, 1.1 Hz, 1 H), 4.05 (s, 1 H),
3.40–3.25 (m, 4 H), 2.15–2.00 (m, 2 H), 1.96–1.84 (m, 4 H), 1.68–1.18
(m, 8 H).
13C NMR (75 MHz, CDCl3): δ = 155.9, 145.2, 111.7, 55.8, 45.6, 35.7,
25.8, 25.7, 22.1.
45.5, 40.3, 25.7, 25.2, 22.9, 17.8.
HRMS (EI+): m/z calcd for C15H26N2O: 250.2045; found: 250.2040.
N-(1-Phenylbut-3-en-2-yl)pyrrolidine-1-carboxamide (9b)3a
Yield: 85 mg (46%), starting from 9a (111 mg, 0.75 mmol); white sol-
id; mp 76–78 °C (EtOAc).
IR (neat): 3280, 2927, 2869, 1619, 1521, 1391, 913, 696 cm–1
.
HRMS (EI+): m/z calcd for C13H22N2O: 222.1732; found: 222.1730.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.13 (m, 5 H), 5.87 (ddd, J = 17.1,
10.4, 5.4 Hz, 1 H), 5.12 (dt, J = 17.1, 1.4 Hz, 1 H), 5.08 (dt, J = 5.4, 1.4
Hz, 1 H), 4.77–4.64 (m, 1 H), 4.11 (d, J = 8.0 Hz, 1 H), 3.37–3.22 (m, 4
H), 2.99–2.81 (m, 2 H), 1.97–1.82 (m, 4 H).
Anal. Calcd for C13H22N2O: C, 70.23; H, 9.97. Found: C, 70.24; H, 10.17.
N-(1-Vinylcyclopentyl)pyrrolidine-1-carboxamide (14b)
Yield: 55 mg (35%), starting from 14a (84 mg, 0.75 mmol); colorless
oil.
13C NMR (75 MHz, CDCl3): δ = 156.2, 139.0, 137.8, 129.8, 128.4, 126.6,
IR (neat): 3336, 2949, 2867, 1626, 1520, 1373, 903 cm–1
.
114.6, 53.0, 45.5, 25.6.
1H NMR (300 MHz, CDCl3): δ = 6.07 (dd, J = 17.4, 10.6 Hz, 1 H), 5.06
(dd, J = 17.4, 1.0 Hz, 1 H), 5.00 (dd, J = 10.6, 1.0 Hz, 1 H), 4.19 (s, 1 H),
3.39–3.15 (m, 4 H), 2.06–1.59 (m, 12 H).
HRMS (EI+): m/z calcd for C15H20N2O: 244.1576; found: 244.1572.
N-(1-Phenylallyl)pyrrolidine-1-carboxamide (10b)3a
13C NMR (75 MHz, CDCl3): δ = 156.2, 143.5, 111.3, 64.6, 45.6, 38.6,
Yield: 90 mg (52%), starting from 10a (100 mg, 0.75 mmol); colorless
oil.
25.7, 23.3.
IR (neat): 3321, 2969, 2869, 1612, 1517, 1390, 1198, 992, 699 cm–1
.
HRMS (EI+): m/z calcd for C12H20N2O: 208.1576; found: 208.1571.
1H NMR (300 MHz, CDCl3): δ = 7.36–7.20 (m, 5 H), 6.05 (ddd, J = 17.3,
10.1, 5.4 Hz, 1 H), 5.64–5.50 (m, 1 H), 5.26–5.21 (m, 1 H), 5.21–5.17
(m, 1 H), 4.51 (d, J = 7.8 Hz, 1 H), 3.41–3.26 (m, 4 H), 1.94–1.82 (m,
4 H).
Anal. Calcd for C12H20N2O: C, 69.19; H, 9.68. Found: C, 69.27; H, 9.94.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

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tert-Butyl {(3aS,4R,7R,7aS)-2,2,2′,2′-Tetramethyl-7-vinyl-7,7a-
dihydro-3aH-spiro[benzo[d][1,3]dioxole-4,4′-[1,3]dioxolan]-7-
yl}carbamate (18)11
References
(1) (a) Christophersen, C.; Holms, A. Acta Chem. Scand. 1970, 24,
1512. For the related [3,3]-sigmatropic rearrangement of allylic
thiocyanates see: (b) Smith, P. A.; Emerson, D. W. J. Am. Chem.
Soc. 1960, 82, 3076. For other examples of [3,3]-sigmatropic
rearrangements see: (c) Ramadhar, T. R.; Kawakami, J.; Batey, R.
A. Synlett 2017, 28, 2865. (d) Ramb, D. C.; Kost, L.; Haufe, G.
Chimia 2014, 68, 436. (e) Mingat, G.; MacLellan, P.; Laars, M.;
Clayden, J. Org. Lett. 2014, 16, 1252.
(2) Overman, L. E.; Kakimoto, M. J. Org. Chem. 1978, 43, 4563.
(3) For the discovery of this reaction, see: (a) Ichikawa, Y. Synlett
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Synlett 2007, 2927. (c) Mailyan, A. K.; Eickhoff, J. A.; Minakova,
A. S.; Gu, Z.; Lu, P.; Zakarian, A. Chem. Rev. 2016, 116, 4441. For
the detailed experimental procedure, see: (d) Ichikawa, Y.;
Kariya, N.; Hasegawa, T. Org. Synth. 2013, 90, 271. For the ste-
reochemistry of the reaction, see: (e) Ichikawa, Y.; Tsoboi, K.;
Isobe, M. J. Chem. Soc., Perkin Trans. 1 1994, 2791.
(4) (a) Whitten, J. P.; Mcarthy, J. R.; Matthews, D. P. Synthesis 1988,
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(5) Enehydroxylamines react with CAP to afford imidazolidinones
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Yield: 6 mg (39%), starting from 17a (11 mg, 0.04 mmol); yield: 11 mg
(35%), starting from 17b (23 mg, 0.08 mmol); yellow oil; [α]D22+9.8 (c
1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 6.10 (d, J = 9.9 Hz, 1 H), 6.04 (dd, J =
16.9, 10.6 Hz, 1 H), 5.90 (d, J = 9.9 Hz, 1 H), 5.26 (d, J = 10.6 Hz, 1 H),
5.22 (d, J = 16.9 Hz, 1 H), 5.08 (s, 1 H), 4.64 (d, J = 7.5 Hz, 1 H), 4.44 (d,
J = 7.5 Hz, 1 H), 4.25 (d, J = 8.8 Hz, 1 H), 3.72 (d, J = 8.8 Hz, 1 H), 1.43 (s,
3 H), 1.42 (s, 9 H), 1.39 (s, 3 H), 1.38 (s, 3 H), 1.33 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 154.7, 138.7, 134.8, 132.2, 115.6, 110.1,
109.0, 79.9, 79.7, 78.7, 78.0, 71.5, 57.4, 28.6, 27.1, 26.7, 26.3, 24.6.
Funding Information
We are grateful to the following agencies for financial support of this
work: Natural Sciences and Engineering Research Council of Canada
(NSERC) (Idea to Innovation and Discovery Grants), Canada Research
Chair Program, Canada Foundation for Innovation (CFI), TDC Research,
Inc., TDC Research Foundation, the Ontario Partnership for Innovation
and Commercialization (OPIC), and The Advanced Biomanufacturing
Centre (Brock University).()
(6) Wilson, R.; Bedard, K.; Baidilov, D.; Tius, M.; Hudlicky, T. Tetra-
hedron Lett. 2018, 59, 2467.
Acknowledgment
(7) Okamoto, R.; Tanaka, K. Org. Lett. 2013, 15, 2112.
(8) Szcześniak, P.; Pieczykolan, M.; Stecko, S. J. Org. Chem. 2016, 81,
1057.
We thank Dr. Liqun Qui (Brock University) and Scott Miskey (Brock
University) for their assistance.
(9) Mainetti, E.; Fresterbank, L.; Malacria, M. Synlett 2002, 923.
(10) Valeev, R. F.; Khasanova, L. S.; Miftakhov, M. S. Russ. J. Org.
Chem. 2010, 46, 670.
Supporting Information
(11) (a) Maehara, T.; Motoyama, K.; Toma, T.; Yokoshima, S.;
Fukuyama, T. Angew. Chem. Int. Ed. 2017, 56, 1549; Angew.
Chem. 2017, 129, 1571. (b) Baidilov, D.; Rycek, L.; Trant, J. F.;
Froese, J.; Murphy, B.; Hudlicky, T. Angew. Chem. Int. Ed. 2018,
57, 10994; Angew. Chem. 2018, 130, 11160.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610659.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E