Synthesis of N-heterocyclic diols by diastereoselective pinacol coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2003.10.191

A series of 5-8 membered N-heterocyclic diols have been prepared from acyclic dicarbonyls via diastereoselective pinacol reactions whereby cis- or trans-diol stereoselectivity is controlled by the choice of low-valent metal reagent used.

Full text of DOI:10.1016/j.tetlet.2003.10.191

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 253–256
Synthesis of N-heterocyclic diols by diastereoselective pinacol
coupling reactions
Sandeep Handa,* Manpreet S. Kachala and Sarah R. Lowe
Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK
Received 24 September 2003; revised 21October 2003; accepted 30 October 2003
Abstract—A series of 5–8 membered N-heterocyclic diols have been prepared from acyclic dicarbonyls via diastereoselective pinacol
reactions whereby cis- or trans-diol stereoselectivity is controlled by the choice of low-valent metal reagent used.
Ó 2003 Elsevier Ltd. All rights reserved.
The pinacol coupling reaction has enjoyed a recent
resurgence as a synthetic method due to the advent of a
variety of low-valent metal reagents capable of affecting
this transformation under mild reaction conditions and
with excellent yields and stereoselectivities.1 However,
whilst the use of intramolecular pinacol couplings for
the generation of carbocycles is well documented,2 there
are relatively few examples of the same reaction being
applied to the synthesis of heterocyclic compounds.
There are several reports of successful pinacol-type
cyclisations of carbonyloxime and carbonylhydrazone
precursors resulting in the formation of N-heterocyclic
amino alcohols mediated by tributyltin hydride–AIBN
or samarium diiodide.3;4 However, to the best of our
knowledge, there are no reported examples of the con-
version of acyclic dicarbonyl compounds to the corre-
sponding N-heterocyclic diols via an intramolecular
pinacol cyclisation. This paper presents our initial
results in this area.
The acyclic precursors required for our studies could be
efficiently accessed from sulfonamide 1 by the route
shown (Scheme 1). Thus alkylation of 1 under basic
conditions generated mixtures of mono- 2a–c and
R
R
X
R
O
O
m
(1-1.2 equiv.)
i. O3, MeOH
ii. Me2S
R
m
n
m
n
+
TsNH2
TsN
TsN
m
K2CO3, acetone
TsN
H
R1
R1
X
1
2
3
4
n
R1
NaH, DMF,
(1-2 equiv.)
a (m=n=0, R=R1=Me)
2a
2b
2c
(64%)
(67%)
(96%)
(50%)
(78%)
(79%)
(72%)
(95%)
4a
4b
4c
4d
4e
4f
(13%, from 1)
(15%, from 1)
(25%, from 1)
(93%, from 2a, X=Br)
(45%, from 2a, X=Br)
(44%, from 2a, X=OTs)
(70%, from 2c, X=Br)
(86%, from 2b, X=Br)
3a
(36%; X=Cl)
(61%; X=Br)
(32%; X=OTs)
b (m=n=1, R=R1=H)
3b
3c
3d
3e
3f
3g
3h
c (m=n=1, R=R1=Me)
d (m=n=0, R=Me, R1=H)
e (m=0, n=1, R=Me, R1=H)
f (m=0, n=1, R=R1=Me)
g (m=n=1, R=Me, R1=H)
h (m=1, n=2, R=R1=H)
4g
4h
Scheme 1.
Keywords: Pinacol couplings; N-Heterocycles; Diols.
* Corresponding author. Tel.: +44-116-2522128; fax: +44-116-2523789; e-mail: s.handa@le.ac.uk
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.191

254
S.Handa et al./ Tetrahedron Letters 45 (2004) 253–256
R
SmI (2.5 eq.),
2
t-BuOH (3 eq.)
Me
OH
H
Me
OH
H
O
O
SmI (2.5 eq.),
2
t-BuOH (3 eq.)
R
TsN
TsN
4c
+
OH
OH
m
m
n
THF
-78 °C to rt
TsN
TsN
THF
-78 °C to rt
n R1
O
HO
7 (11%)
R1
6 (47%)
4
5
Scheme 3.
Scheme 2.
bis-alkylated 3a–c sulfonamides, which were readily
separated by column chromatography.5 A second
alkylation step then allowed preparation of a series of
unsymmetrical dienes 3d–h from 2a–c. Subsequent
ozonolysis of the dienes 3 followed by reductive work-
up gave the requisite dicarbonyl compounds 4 in good
to excellent yields after purification by chromatography.6
stereochemical assignments of diols 5a–h were made on
the basis of NMR studies and X-ray crystallography for
suitable solids.9
Pleasingly the SmI2-mediated reactions were successful
in furnishing pyrrolidines (entries 1–2) and piperidine-
diols (entries 3–4) in good yields and with complete
diastereoselectivity for the cis-diol. These results are
comparable to those found with the corresponding
carbocyclic systems.2 Perhaps not surprisingly reactions
to form seven- and eight-membered heterocycles (entries
5, 6 and 8) were less efficient and proceeded with lower
levels of stereocontrol producing appreciable amounts
of trans-diol (cis:trans ratios were determined from
NMR analysis). However the cis-diols could be isolated
pure from these reactions by careful chromatography.
Interestingly reaction of diketone 4c gave none of the
anticipated diol (entry 7). Instead the two 6-membered
heterocycles 6 (47%) and 7 (11%) were isolated from the
reaction mixture as single diastereoisomers (Scheme 3,
stereochemistry assigned by X-ray crystallography9).
The formation of these unexpected products can be
explained by an intramolecular aldol condensation of 4c
to produce ketone 6, which is subsequently reduced
stereoselectively by SmI2 to the diol 7. Catalysis of the
aldol reaction may be facilitated by some Sm3þ species
present in solution, however the reasons for the forma-
tion of these products in preference to the seven-mem-
bered diol are not clear.10
With the required precursors in hand we turned
our attention to investigating the samarium diiodide-
mediated pinacol coupling reaction of these systems
(Scheme 2). Thus a THF solution (ca. 0.1M) of the
appropriate dicarbonyl compound 4a–h and t-BuOH
(3 equiv) was added dropwise to a solution of SmI2 [ca.
0.1M in THF, prepared 7 from Sm (3 equiv) and CH2I2
(2.5 equiv)] at )78 °C and the reaction allowed to warm
to room temperature over 12 h. Work-up and chroma-
tography resulted in the isolation of the corresponding
diols 5a–h in moderate to good yields (Table 1).8 The
Table 1. Diols produced via Scheme 2
Entry
Dicarbonyl
Product diols 5 (overall yield)
R
OH
TsN
OH
R1
1
2
4a
4d
5a R ¼ R1 ¼ Me (62%)
5d R ¼ Me, R1 ¼ H (50%)
Having successfully completed the synthesis of a number
of heterocyclic cis-diols we next turned our attention to
accessing the corresponding trans-isomers. Itoh and co-
workers have recently reported the use of Cp2TiPh
[generated in situ from Cp2Ti(Ph)Cl (3 mol %) and Zn
(1equiv)] as a catalyst for trans-selective intramolecular
pinacol couplings to produce carbocyclic diols.11 How-
ever there are no successful reports of the application of
this reagent for the production of N-heterocycles.
Indeed the failure of stoichiometric Cp2TiPh to produce
a hexahydroazepine from the pinacol-type coupling of
an acylic carbonylhydrazone has been noted.4 Reaction
of a selection of dicarbonyl compounds 4 with 3 equiv of
Cp2TiPh (prepared by treatment of Cp2TiCl2 with
i-PrMgCl and then PhMgBr)12 in THF at room tem-
perature for 12–18 h gave, after chromatography, the
products indicated (Table 2).13 It can be seen that this
low-valent Ti3þ species successfully produces pyrrolidine
and piperidine derived trans-diols (entries 1–4) from the
corresponding acyclic precursors. Although levels of
diastereoselectivity are not as high as in the SmI2-med-
iated reaction the trans-diol could be isolated in pure
R
OH
OH
R1
TsN
3
4
4e
4f
5e R ¼ Me, R1 ¼ H (62%)
5f R ¼ R1 ¼ Me (73%)
R
OH
TsN
OH
R1
5
6
7
4b
4g
4c
5b R ¼ R1 ¼ H (37%; cis:trans, 4:1)a
5g R ¼ Me, R1 ¼ H (25%)
5c R ¼ R1 ¼ Me (0%––see text)
OH
TsN
OH
8
4h
5h (16%; cis:trans, 3:1)a
a Product ratios are calculated from 1H and 13C NMR. Only the cis-
diols were isolated pure, 16% from 4b and 10% from 4h.

S.Handa et al./ Tetrahedron Letters 45 (2004) 253–256
255
Table 2. Diols produced via reaction of 4 with Cp2TiPh
5. All new compounds gave satisfactory spectroscopic and
microanalytical and/or HRMS analysis.
6. Attempts to prepare 3i and 3j via the route shown (Scheme
1) were unsuccessful due to the instability of these dials. In
the case of 3i only the hydrate 9 could be isolated
Entry
Dicar-
bonyl
Product diols 8 (yield)
R
OH
TsN
OH
R1
OH
O
O
TsN
O
8a R ¼ R1 ¼ Me (64% + 5% cis-isomer 5a)a
TsN
1
2
4a
4d
TsN
O
8d R ¼ Me, R1 ¼ H (59% + 18% cis-isomer 5d)a
O
OH
R
OH
3i
3j
9
OH
R1
TsN
7. Molander, G. A.; Kenny, C. J.Org.Chem. 1991, 56, 1439–
1445.
3
4
4e
4f
8e R ¼ Me, R1 ¼ H (37%)
8. Selected spectroscopic data for cis-diols 5:
5a: 1H NMR (400 MHz, CDCl3) d ¼ 1:14 (6H, s), 2.43
(3H, s), 3.31(2H, d, J 10.2 Hz), 3.35 (2H, d, J 10.2 Hz),
7.32 (2H, d, J 8.0 Hz), 7.71(2H, d, J 8.0 Hz); 13C NMR
(100.6 MHz, CDCl3) d ¼ 20:49, 21.54, 57.86, 77.99,
127.45, 129.67, 133.87, 143.63.
8f R ¼ R1 ¼ Me (53% + 9% cis-isomer 5f)a
5
6
4b
4h
No identifiable products isolated
No identifiable products isolated
a Stereoisomers were separated by column chromatography.
1
5b: H NMR (250 MHz, CDCl3) d ¼ 1:71–1:83 (2H, m),
1.98–2.12 (2H, m), 2.42 (3H, s), 3.18 (2H, ddd, J 13.5, 7.8
and 4.0 Hz), 3.41(2H, ddd, J 13.5, 7.8 and 4.4 Hz), 3.95
(2H, dd, J 6.0 and 2.1Hz), 7.30 (2H, d, J 8.0 Hz), 7.65 (2H,
d, J 8.0 Hz); 13C NMR (62.9 MHz, CDCl3) d ¼ 21:46,
30.94, 42.08, 72.33, 126.97, 129.71, 135.65, 143.31.
5d: 1H NMR (400 MHz, CDCl3) d ¼ 1:24 (3H, s), 2.43 (3H,
s), 3.16 (1H, dd, J 10.5 and 5.5 Hz), 3.26 (1H, d, J 10.5 Hz),
3.29 (1H, d, J 10.5 Hz), 3.59 (1H, dd, J 10.5 and 5.5 Hz),
3.81(1H, app.t, J 5.5 Hz), 7.33 (2H, d, J 8.0 Hz), 7.70 (2H,
d, J 8.0 Hz); 13C NMR (100.6 MHz, CDCl3) d ¼ 21:55,
23.04, 52.73, 57.16, 75.16, 76.16, 127.54, 129.71, 133.61,
143.72.
form and in moderate to good yields. The failure of the
Cp2TiPh reagent to furnish seven- and eight-membered
rings (entries 5–6) is in accordance with the analogous
reactions of carbonylhydrazones.4
In conclusion we have reported the first successful dia-
stereoselective pinacol coupling reactions of dicarbonyl
species to produce N-protected heterocyclic diols.14 This
synthetic route complements the alternative approach
based on a ring closing metathesis-dihydroxylation
strategy.15 We are currently investigating both these ap-
proaches for the synthesis of more complex heterocycles.
5e: 1H NMR (400 MHz, CDCl3) d ¼ 1:30 (3H, s), 1.79–
1.86 (2H, m), 2.44 (3H, s), 2.69 (1H, d, J 11.8 Hz), 2.68–
2.76 (1H, m), 3.05 (1H, dd, J 11.8 and 1.3 Hz), 3.30–3.38
(2H, m), 7.34 (2H, d, J 8.0 Hz), 7.64 (2H, d, J 8.0 Hz); 13
C
NMR (100.6 MHz, CDCl3) d ¼ 21:52, 22.88, 29.71, 43.54,
53.96, 69.89, 71.94, 127.64, 129.79, 132.99, 143.87.
5f: 1H NMR (400 MHz, CDCl3) d ¼ 1:16 (3H, s), 1.31 (3H,
s), 1.77 (2H, dd, J 5.0 and 6.6 Hz), 2.44 (3H, s), 2.85 (1H, d,
J 11.2 Hz), 2.94 (1H, dt, J 11.5 and 6.6 Hz), 3.03 (1H, dd, J
11.2 and 1.1 Hz), 3.15–3.20 (1H, m), 7.33 (2H, d, J 8.0 Hz),
7.63 (2H, d, J 8.0 Hz); 13C NMR (100.6 MHz, CDCl3)
d ¼ 21:31, 21.47, 22.61, 35.72, 42.83, 53.16, 71.67, 72.39,
127.53, 129.71, 133.1, 143.67.
Acknowledgements
The authors thank the EPSRC for a studentship (GR/
N24391to MSK) and to J. Fawcett (Leicester) for
carrying out the X-ray crystallographic studies.
1
5g: H NMR (400 MHz, CD3OD) d ¼ 1:22 (3H, s), 1.60
References and Notes
(1H, ddd, J 15.0, 8.0 and 3.5 Hz), 1.75 (1H, ddt, J 15.0, 7.8
and 3.0 Hz), 1.93–2.02 (2H, m), 2.45 (3H, s), 3.15 (1H, ddd,
J 13.5, 8.0 and 3.0 Hz), 3.26 (1H, ddd, J 13.5, 8.0 and 3.0
Hz), 3.37–3.46 (2H, m), 3.47 (1H, dd, J 8.0 and 3.0 Hz),
7.41(2H, d, J 8.0 Hz), 7.69 (2H, d, J 8.0 Hz); 13C NMR
(100.6 MHz, CD3OD) d ¼ 20:44, 25.41, 31.47, 36.68,
41.62, 42.17, 73.10, 75.79, 127.15, 129.83, 136.11,
143.83.
1. Wirth, T. Angew.Chem,. Int.Ed. 1996, 35, 61–63.
2. For selected examples see: (a) Carpintero, M.; Jaramillo,
ꢀ
C.; Fernandez-Mayoralas, A. Eur.J.Org.Chem.
2000,
1285–1296; (b) Hays, D. S.; Fu, G. C. J.Org.Chem. 1998,
63, 6375–6381; (c) Storch de Gracia, I.; Dietrich, H.;
Bobo, S.; Chiara, J. L. J.Org.Chem. 1998, 63, 5883–5889;
(d) Kang, M.; Park, J.; Konradi, A. W.; Pedersen, S. F. J.
Org.Chem. 1996, 61, 5528–5531; (e) Chiara, J. L.; Cabri,
W.; Hanessian, S. Tetrahedron.Lett. 1991, 32, 1125–1128.
3. (a) Kiguchi, T.; Okazaki, M.; Naito, T. Heterocycles 1999,
51, 2711–2722; (b) Naito, T.; Nakagawa, K.; Nakamura,
T.; Kasei, A.; Ninomiya, I.; Kiguchi, T. J.Org.Chem.
1999, 64, 2003–2009; (c) Miyabe, H.; Torieda, M.; Inoue,
K.; Tajiri, K.; Kiguchi, T.; Naito, T. J.Org.Chem. 1998,
63, 4397–4407; (d) Miyabe, H.; Kanehira, S.; Kume, K.;
Kandori, H.; Naito, T. Tetrahedron 1998, 54, 5883–5892.
4. Riber, D.; Hazell, R.; Skrydstrup, T. J.Org.Chem. 2000,
65, 5382–5390.
1
5h: H NMR (250 MHz, CD3OD) d ¼ 1:64–2.05 (6H, m),
2.41(3H, s), 2.71(1H, ddd, J 13.7, 6.2 and 4.4 Hz), 2.81
(1H, ddd, J 13.9, 7.8 and 3.7 Hz), 3.41–3.56 (2H, m), 3.94
(1H, dt, J 8.5 and 3.0 Hz), 4.13 (1H, dt, J 8.5 and 3.0 Hz),
7.38 (2H, d, J 8.0 Hz), 7.65 (2H, d, J 8.0 Hz); 13C NMR
(62.9 MHz, CD3OD) d ¼ 21:42, 26.42, 30.78, 32.87, 46.10,
49.23, 73.53, 73.72, 128.21, 130.85, 136.67, 144.92.
9. Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers: 5a, CCDC
218780; 5h, CCDC 218781; 6, CCDC 218782; 7, CCDC
218783. Copies of the data can be obtained, free of

256
S.Handa et al./ Tetrahedron Letters 45 (2004) 253–256
charge, on application to CCDC, 12 Union Road,
4.0 Hz), 2.45 (3H, s), 2.80 (1H, d, J 12.0 Hz), 2.95–3.06
(1H, m), 3.05 (1H, d, J 12.0 Hz), 3.07–3.17 (1H, m), 3.50
(1H, br s), 7.34 (2H, d, J 8.0 Hz), 7.65 (2H, d, J 8.0 Hz);
13C NMR (100.6 MHz, CDCl3) d ¼ 20:77, 21.51, 28.95,
42.65, 53.47, 70.69, 72.45, 127.62, 129.77, 132.99,143.81.
8f: 1H NMR (250 MHz, CDCl3) d ¼ 1:17 (3H, s), 1.25
(3H, s), 1.47 (1H, d app.t, J 14.0 and 3.0 Hz), 1.58–1.68
(2H, br s) 2.07 (1H, ddd, J 14.0, 12.8 and 5.0 Hz), 2.44
(3H, s), 2.61(1H, ddd, J 13.0, 12.8 and 3.0 Hz), 2.71 (1H,
d, J 11.5 Hz), 3.29 (1H, dd, J 11.5 and 2.0 Hz), 3.52–3.61
Cambridge CB2 1EZ, UK [fax: +44-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
10. For reports of analogous aldol side products occurring in
SmI2-mediated pinacol reactions see: (a) Uenishi, J.;
Masuda, S.; Wakabayashi, S. Tetrahedron Lett. 1991, 32,
5097–5100; (b) Chuang, T. H.; Fang, J. M.; Jiaang, W. T.;
Tsai, Y. M. J.Org.Chem. 1996, 61, 1794–1805.
11. (a) Yamamoto, Y.; Hattori, R.; Miwa, T.; Nakagai, Y.;
Kubota, T.; Yamamoto, C.; Okamoto, Y.; Itoh, K. J.Org.
Chem. 2001, 66, 3865–3870; (b) Yamamoto, Y.; Hattori,
R.; Itoh, K. Chem.Commun. 1999, 825–826.
(1H, m), 7.33 (2H, d, J 8.0 Hz), 7.64 (2H, d, J 8.0 Hz). 13
C
NMR (62.9 MHz, CDCl3+10% CD3OD) d ¼ 19:40, 21.31,
22.74, 34.68, 42.26, 52.78, 70.67, 71.50, 127.48, 129.68,
132.76, 143.79.
12. (a) Teuben, J. H. J.Organomet.Chem. 1973, 57, 159–167;
(b) Teuben, J. H.; De Liefde Meijer, H. J. J.Organomet.
Chem. 1972, 46, 313–321.
14. In preliminary experiments we have been able to efficiently
remove the p-toluenesulfonyl protecting group using Na–
NH3(l), for example
13. Selected spectroscopic data for trans-diols 8:
8a: 1H NMR (250 MHz, CDCl3) d ¼ 1:23 (6H, s), 1.51–
1.68 (2H, br s), 2.42 (3H, s), 3.32 (2H, d, J 10.8 Hz), 3.47
(2H, d, J 10.8 Hz), 7.31 (2H, d, J 8.0 Hz), 7.73 (2H, d, J
8.0 Hz); 13C NMR (62.9 MHz, CDCl3) d ¼ 17:58, 21.51,
58.98, 79.94, 127.45, 129.64, 134.22, 143.53.
Me
TsN
Me
HN
OH
OH
Me
OH
OH
Me
Na
8d: 1H NMR (250 MHz, CDCl3) d ¼ 1:21(3H, s), 2.38
(3H, s), 3.18 (1H, d, J 10.5 Hz), 3.25 (1H, d, J 10.5 Hz),
3.12–3.25 (1H, m), 3.64 (1H, dd, J 10.5 and 4.6 Hz), 3.83–
3.90 (1H, m), 7.28 (2H, d, J 8.0 Hz), 7.67 (2H, d, J 8.0 Hz);
13C NMR (62.9 MHz, CDCl3) d ¼ 19:57, 21.46, 54.39,
57.37, 76.84, 79.06, 127.42, 129.68, 133.56, 143.68.
8e: 1H NMR (250 MHz, CDCl3) d ¼ 1:29 (3H, s), 1.61–
1.74 (1H, m+2H, br s), 2.09 (1H, dd app.t, J 13.8 and
NH3(liq.)
5f
90%
15. For a recent example see: Takahata, H.; Banba, Y.; Ouchi,
H.; Nemoto, H.; Kato, A.; Adachi, I. J.Org.Chem. 2003,
68, 3603–3607.