Progress towards the Stereoselective Synthesis of 3,6-Disubstituted 1,2-Diamino-4-cyclohexenes by Ring Closing Metathesis Reaction

Article abstract of DOI:10.1002/1615-4169(200212)344:10<1068::AID-ADSC1068>3.0.CO;2-S

The ring closing metathesis of 4(R),5(R)-bis[1(S)-phenylethylamino]-3,6-diethenyl-1,7-octadiene required the preliminary formation of the cyclic formaldehyde aminal, then the use of the Grubbs' ruthenium benzylidene complex (10 mol %) in refluxing toluene

Full text of DOI:10.1002/1615-4169(200212)344:10<1068::AID-ADSC1068>3.0.CO;2-S

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Progress towards the Stereoselective Synthesis
of 3,6-Disubstituted 1,2-Diamino-4-cyclohexenes
by Ring Closing Metathesis Reaction
Stefano Grilli, Gianluca Martelli, Diego Savoia,* Carla Zazzetta
¡
Dipartimento di Chimica ™G. Ciamician∫, Universita di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax: ( ‡ 39)-51-2099456, e-mail: savoia@ciam.unibo.it
Received: July 31, 2002; Accepted: September 24, 2002
Abstract: The ring closing metathesis of 4(R),5(R)-
R
R
R
R
R
R
Me
Ph
Me
Ph
bis[1(S)-phenylethylamino]-3,6-diethenyl-1,7-octadi-
ene required the preliminary formation of the cyclic
formaldehyde aminal, then the use of the Grubbs×
ruthenium benzylidene complex (10 mol %) in re-
fluxing toluene in the presence of 2 equivalents of
trifluoroacetic acid. The cyclic aminal was cleaved in
situ after the cyclisation step, so that the final
product was the 1,2-diamino-3,6-diethenylcyclohex-
4-ene derivative. The predominant C1-symmetric
diastereomer was isolated with 48% yield.
Me
Ph
Me
Ph
NH HN
H2N
NH2
NH HN
2
3
1
a: R = H
b: R = CH=CH2
c: R = Ph
Scheme 1. Synthetic route to 3,6-disubstituted 1,2-diamino-
cyclohexanes.
N
N
Mes
Mes
Ph
Cy3P
Keywords: diamine; diene; ring closing metathesis;
ruthenium
Cl
Cl
Ru
Ru
Cl
Cl
Ph
PCy3
PCy3
4
5
Figure 1. Ruthenium carbene complexes used for RCM
We have recently envisioned that the 1,2-diaminocyclo- reactions.
hexane backbone can be constructed by applying
transition metal-mediated or -catalysed cyclisation
procedures to 4,5-diamino-1,7-octadiene derivatives,
Here we describe the results of the RCM reactions we
which are in turn available by the diastereoselective have carried out on the 3,6-disubstituted 4(R),5(R)-
double addition of allylic organometallic reagents to the bis[1(S)-phenylethylamino]-1,7-octadienes 1b[1b] and
enantiopure 1,2-diimine derived from glyoxal and (S)- 1c[1c] (Scheme 1) using as catalysts ruthenium carbene
or (R)-1-phenylethylamine.[1] We have recently describ- complexes, i.e., the Grubbs× catalyst 4 and the more
ed reductive cyclozirconation reactions of the diamine recently described catalyst 5, which bears a N-hetero-
1a,[1a] leading to different diastereomers of 4,5-dimethyl- cyclic carbene ligand[3nÀq,6] (Figure 1). The results
1(R),2(R)-diaminocyclohexanes.[2] We have also ex- obtained on 1b and its derivative 6 (Scheme 2) are
ploited the ring closing metathesis (RCM)[3] reaction reported in Table 1. These compounds feature the
to convert the bis(hydrochloride) of the diamine 1a to presence of diastereotopic vinyl groups, which should
the diaminocyclohexene 2a (Table 1, entry 1) using the be discriminated by the ruthenium catalyst owing to the
ruthenium carbene complex 4 as the catalyst (Figure 1), presence of the stereogenic centres at C-4 and C-5, so
then the saturated primary diamine 3a was prepared that two new stereocentres and possibly three diaster-
by hydrogenation-hydrogenolysis (Scheme 1).[4] These eomers are formed in the cyclic product.[7] The protocol
cyclisation reactions opened new routes to ring-substi- applied to 1b was the same as that which previously
tuted 1,2-diaminocyclohexanes. In our opinion, it is worked successfully with 1a[4] and involved the prelimi-
worth studying the influence that substituents/stereo- nary formation of the diamine bis(hydrochloride). In
centres at the C-3 and C-6 positions of the 1,2- fact, the usual protection of the amino function as an
diaminocyclohexane skeleton can have in asymmetric amide or carbamate, which is generally adopted to
reactions where N-derivatives of (R,R)- and (S,S)-1,2- perform RCM reactions of aminodienes, could be
diaminocyclohexane 3a have acted as effective cata- accomplished for only one of the two amino functions
lysts.[5]
of compounds 1a c, even using an excess of the most
1068
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Adv. Synth. Catal. 2002, 344, No. 10

Towards Stereoselective Synthesis of 3,6-Disubstituted 1,2-Diamino-4-cyclohexenes
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extracted with CH2Cl2 and analysed (GC-MS and
1H NMR). The failure of the cyclisation was attributed
to steric factors, owing to the double allylic substitution
of the 1,7-octadiene chain. Therefore, more forcing
reaction conditions were applied, but only ca. 3%
conversion of 1b to 2b after 24 h in refluxing benzene
was determined by GC-MS analysis (entry 2). We then
turned ourattention to the catalyst 5 and first checked its
activity in the acidic conditions required by the
substrate: the RCM reaction of 1a-2 HCl in CH2Cl2 at
40 8C with a 10% loading of 5 gave an almost quan-
titative conversion to 2a after 1 h (entry 3). Then the
cyclisation of 1b-2 HCl was attempted in refluxing
toluene (110 8C), but after repeated additions of the
catalyst for an overall amount of 30 mol % during 24 h,
2b was formed in 30% yield as a mixture of two
diastereomers (dr 82:18), most of the substrate 1b being
recovered (entry 4).
HCHO (12 equiv.),
p-TsOH (cat.)
Me
Ph
Me
Ph
CH2Cl2, MgSO4, 3 d
Me
N
N
Me
Ph
NH HN
Ph
1b
6
1) 2 HX
1) 2 HCl
2) 4 or 5 (cat.)
2) 4 or 5
3) NaOH
3) NaOH
Me
Ph
Me
Ph
NH HN
Me
N
N
Me
Ph
2b
Ph
7
chromatography
(SiO2 column)
S
R
S
S
R
R
Me
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
+
+
NH HN
NH HN
NH HN
Ph
We reasoned that the moderate efficiency of the RCM
reactions was in part due to the difficulty to attain the
required conformation where the terminal alkene
moiety is close to the initially formed ruthenacyclobu-
tane complex.[8] Aiming to overcome this obstacle, we
decided to reduce the rotational freedom of the carbonic
chain by reversible formation of the imidazolidine ring,
as in 6. This compound was slowly but quantitatively
obtained by the acid-catalysed reaction of 1b with
paraformaldehyde (Scheme 2). However, no reaction
occurred when 6 was treated with 10 mol % of catalyst 4
in benzene solution, even at reflux, avoiding the
preliminary acidification step. With this regard, it
should be observed that a few examples of successful
(S,S)-2b
(R,R)-2b
(S,R)-2b (major)
2 TFA,
toluene,
110
HCHO (12 equiv.),
p-TsOH (cat.)
CH2Cl2, MgSO4, 3 d
C
S
R
Me
N
N
Me
Ph
Ph
(S,R)-7
Scheme 2. Diastereoselective RCM reactions of diaminote-
traene derivatives.
reactive acyl and sulphonyl halides. This is probably due RCM reactions of 1,n-dienes in the presence of tertiary
to steric hindrance in the second protection step. amine functions have been described.[9]
Unfortunately, working on 1b-2 HCl and using
Successively, working on 6-2 HCl with 4 in refluxing
10 mol % of the Grubbs× catalyst 4 in CH2Cl2 at room toluene no reaction was observed after 3 h (entry 5).
temperature, complete recovery of the starting com- Instead, substitution of trifluoroacetic acid (TFA) for
pound 1b was observed after 12 h, at which time the hydrochloric acid allowed us to obtain the bicyclic
mixture was made basic and the organic material was product 7 with 54% yield using the catalyst 4 (10 mol %)
Table 1. RCM reactions of substituted 1,7-octadienes.
Entry
Substrate
Catalyst,
[mol %]
Solvent
Temp.
[8C]
Time
[h]
Products, yield
[%] (GC)
dr of 2b[a]
1
2
3
4
5
6
7
8
1a-2 HCl
1b-2 HCl
1a-2 HCl
1b-2 HCl
6-2 HCl
6-2 TFA
6-2 TFA
6-2 TFA
4, 3
CH2Cl2
benzene
CH2Cl2
toluene
toluene
Benzene
toluene
toluene
25
80
40
110
110
80
110
110
6
24
1
20
3
5
7
3
2a, 73[b]
2b, 3
2a, 99
2b, 30
4, 10
5, 10
5, 30[c]
4, 10
4, 10
5, 10
4, 10
0: 88: 12
7, 54[d]
7, 12;[e] 2b, 88
2b, 100
5: 60: 35
0: 83: 17
[a]
According to the order of elution.
Isolated yield.
The catalyst was added in 3 portions every 6 h.
dr 4: 83: 13; no reaction occurred in the absence of TFA.
dr 70: 30.
[b]
[c]
[d]
[e]
Adv. Synth. Catal. 2002, 344, 1068 1072
1069

Stefano Grilli et al.
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in refluxing benzene after 5 h (entry 6); in this case, the cyclic aminal 7 to the secondary diamine 2b posed us the
three diastereomers of 7 were formed with dr 4:83:13, problem of determining the cause of the aminal cleav-
according to the order of elution in the GC-MS analysis. age, so we prepared the compound (S,R)-7, which we
Hence, the use of trifluoroacetic acid instead of HCl was had not isolated previously, by treatment of the diamine
determinant for preserving the activity of the carbene (S,R)-2b with paraformaldehyde(Scheme 2). Treatment
catalyst even at the high temperature, so allowing us to of (S,R)-7 with the Grubbs× catalyst 4 in refluxing
increase the yield of the metathesis product. Then, toluene left the substrate unchanged after 3 h, whereas
aiming to increase the reaction rate, we used the catalyst the alternative reaction with TFA (2 equivalents) in
5 (10 mol %) in refluxing toluene and were gratified to refluxing toluene for 3 h caused its almost complete
observe the quantitative cyclisation of 6-2 TFA after 7 h transformation to (S,R)-2b, presumably owing to the
(entry 7), but, unexpectedly, the reaction mixture was presence of water (Scheme 2). We could also demon-
composed of the secondary diamine 2b (88% by GC-MS strate that the cleavage of the aminal function followed
analysis) and the bicyclic aminal 7 (12% yield), both the RCM reaction since, in a separate experiment, the
compounds being mixtures of diastereomers with aminal 6 was completely recovered after treatment with
comparable ratios. Finally, the best result was achieved 2 equivalents of TFA in refluxing toluene for 5 h.
when 6-2 TFA was heated in refluxing toluene in the
The protocol which proved successful for the cyclisa-
presence of the Grubbs× catalyst 4 (10 mol %): after only tion of 1b to 2b was then applied to the diaminodiene
3 h, the complete conversion to 2b with high diaster- (R,R)-1c[1c] carrying a phenyl substituent in both the
eoselectivity (dr 83:17) was obtained (entry 8). The two allylic positions, despite the presumed difficulty to
diastereomers of 2b obtained in entry 8 were separated obtain good results, owing to the steric hindrance
by column chromatography: the major one (48%) had C1 exerted by the Ph group in the alkene-Ru complexation
symmetry (1H NMR analysis), hence we safely assigned steps. Thus, the aminal 8 was routinely prepared and
to it the configuration of (S,R)-2b, referring only to the submitted to the reactions conditions which were
newly created stereocentres (Scheme 2). On the other optimal for 6: 2 equivalents of TFA, 10 mol % of 4,
hand, the minor diastereomer (8%) had C2-symmetry toluene, 110 8C, 3 h (Scheme 3), but less than 10%
and presumably is (S,S)-2b; in fact, the trans,trans,trans conversion to the diamine (R,R)-2c was observed, and
disposition of the ring substituents was suggested by the several unidentified by-products were formed; more-
coupling constants (J ˆ 6.2 Hz) of the ring methyne over, no progress of the RCM reaction was observed
protons NCHCHN and comparison with the subse- after further 3 h. It is noteworthy that the bicyclic aminal
quently prepared compound (R,R)-2c (Scheme 3).
which should be formed as an intermediate in the first
The superior performance of the carbene complex 4 step was not detected in the reaction mixture. Unfortu-
with respect to the second-generation complex 5 is nately, (R,R)-2c was not obtained pure by column
surprising, but can be explained by considering that 5 chromatography of the crude product, but its structure
1
bears a basic heterocyclic carbene ligand, which can was confirmed by H NMR analysis of an enriched
undergo decomposition by the acid at high temper- sample.
ature.[10] It is also noteworthy that when the progress of
In conclusion, it should be observed that the Grubbs×
the reaction (entry 8) was monitored over time by GC- catalyst has been rarely employed to catalyse RCM
MS analysis, the formation of the intermediate 7 and its reactions at such a high temperature. To the best of our
progressive conversion to 2b was demonstrated. It knowledge, there are only two reports describing that
should be also underlined that the same result was such reactions are possible in toluene at 100 or 110 8C,[11]
obtained in different runs. The in situ conversion of the although the alkene isomerisation is a competitive
reaction under these conditions.[12,13] Further studies
are needed to find the optimal reaction conditions for
the RCM of diaminodienes carrying bulky allylic
substituents, e.g., 1c, for example, by using the molyb-
Ph
Me
R
R
Ph
Me
denum-based Schrock×s catalyst,[5] which is less sensitive
to steric hindrance with respect to the ruthenium-based
catalysts, but is more expensive and less practical to be
used.
NH HN
Ph
Ph
(R,R)-1c
HCHO (12 equiv.), MgSO4,
p-TsOH (cat.), CH2Cl2
Experimental Section
Ph
Me
Ph
Me
Ph
Me
R
R
Ph
Me
2 TFA, 4 (10 mol %)
toluene, 110 C, 3 h
NH HN
N
N
Ph
Ph
General Information
Ph
Ph
(R,R)-2c, <10%
8
Melting points are uncorrected. Solvents were distilled over
the appropriate drying agent in N2 atmosphere before use:
Scheme 3. RCM reaction of the diaminodiene (R,R)-1c.
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Adv. Synth. Catal. 2002, 344, 1068 1072

Towards Stereoselective Synthesis of 3,6-Disubstituted 1,2-Diamino-4-cyclohexenes
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benzene and toluene (Na, then LiAlH4), CH2Cl2 (P2O5).
Optical rotations were measured on a digital polarimeter in a
1-dm cell and [a]D values are given in 10À1 deg cm3 gÀ1.
1H NMR spectra were recorded on a Varian Gemini instru-
ment at 300 or 200 MHz for samples in CDCl3 which was stored
2 min, 40% NaOH (10 mL) was carefully added to the cooled
(0 8C) mixture, and the organic phase was extracted with
CH2Cl2 (3 Â 20 mL). The collected organic layers were dried
(Na2SO4) and concentrated to leave a dark brown oil, which
was chromatographed on an SiO2 column eluting with cyclo-
hexane-ethyl acetate, 20:1, to give the two diastereomers of 2b.
N,N×-Bis[1(S)-phenylethyl)]-1(R),2(R)-diamino-3(S),6(R)-
diethenylcyclohex-4-ene [(S,R)-2b]: yellow oil, yield: 0.346 g
1
over Mg: H chemical shifts are reported in ppm relative to
CHCl3 (dH ˆ 7.27) and J values are given in Hz. Mass spectra
were taken at an ionising voltage of 70 eV on a Hewlett-
Packard 5970 or 5890 spectrometer with GLC injection.
Chromatographic separations were performed on columns of
SiO2 (Merck, 230 400 mesh) at medium pressure. The
catalysts 4 and 5 were purchased from Aldrich. All the
organometallic reactions were performed in a flame-dried
apparatus under a static atmosphere of dry N2.
1
(48%); [a]20: À 116.3 (c 0.96, CHCl3); H NMR (200 MHz,
CDCl3): d ˆD 7.35 (m, 10H, Ph), 5.87 4.98 (m, 8 H, vinyl), 3.93
and 3.81 (2 q, J ˆ 6.8 Hz, 2H, CHMe), 3.08 and 2.65 (2 m, 2H,
ˆ
CHCH CH2), 2.40 (dd, J ˆ 5.2 and 11.0 Hz, 1H, NCHCHN),
2.26 (dd, J ˆ 8.4 and 11.0 Hz, 1H, NCHCHN), 1.36 and 1.23 (2
d, J ˆ 6.8 Hz, CHMe); 13C NMR (300 MHz): d ˆ 146.1, 145.1,
142.0, 136.9, 130.1, 128.4, 128.1, 127.8, 127.0, 126.8, 126.7, 126.5,
117.6, 115.2, 57.0, 55.7, 55.3, 53.8, 51.2, 41.9, 25.5, 24.6.; MS: m/z
(relative intensity) ˆ 105 (100), 266 (18), 161 (18), 134 (17), 79
‡
Preparation of Formaldehyde Aminals
(14), 238 (6), 372 (M , 1); anal. calcd. for C26H32N2: C 83.82, H
8.66, N 7.52%; found: C 83.84, H 8.67, N 7.49%.
The mixture of the diamine 1b (2.0 g, 5 mmol), paraformalde-
hyde (1.5 g, 0.06 mol), p-toluenesulphonic acid (10 mg) and
anhydrous MgSO4 (15 g) in CH2Cl2 (75 mL) was stirred at
room temperature for 3 d, then was filtered through a Celite
pad, and the organic phase was washed with H2O (25 mL), then
dried again with Na2SO4, and concentrated to leave the aminal
6 as a yellow thick oil; yield: 2.01 g (97%). The aminals were
used as obtained, avoiding any purification.
N,N×-Bis[1(S)-phenylethyl)]-1(R),2(R)-diamino-3(S),6(S)-
diethenylcyclohex-4-ene [(S,S)-2b]: yield: 0.072 g (relatively
impure due to the presence of tricyclohexylphosphine);
1H NMR (300 MHz, CDCl3): d ˆ 7.38 7.20 (m, 10H, Ph),
ˆ
ˆ
5.74 (m, 2H, CH CH2), 5.25 (s, 2H, CH CH), 5.08 (m, 4H,
ˆ
CH CH2), 4.0 (q, J ˆ 6.6 Hz, 2H, CHMe), 2.64 (m, 2H,
ˆ
CHCH CH2), 2.23 (d, J ˆ 6.5 Hz, 2H, NCHCHN), 1.26 (br,
2H, NH), 1.21 (d, J ˆ 6.6 Hz, 6H, CHMe).
N,N×-Bis[1(S)-phenylethyl)]-4(R),5(R)-di(1-ethenyl-2-pro-
penyl)imidazolidine (6): [a]20: ‡ 2.3 (c 1.08, CHCl3); 1H NMR
(200 MHz, CDCl3): d ˆ 7.35D 7.10 (m, 10H, Ph), 6.08 5.77 (m,
N,N×-Bis[1(S)-phenylethyl)]-1(R),2(R)-diamino-3(R),6(R)-
diphenylcyclohex-4-ene [(R,R)-2c]: yield: 0.055 g (ca. 75%
pure by 1H NMR); 1H NMR (200 MHz, CDCl3): d ˆ 7.58 7.0
ˆ
ˆ
4H, CH CH2), 5.19 4.90 (m, 8H, CH CH2), 3.95 (q, J ˆ
ˆ
(m, 16H, Ph), 6.91 (m, 4H, Ph), 5.48 (s, 2H, CH CH), 3.32 (m,
7.0 Hz, 2H, CHMe), 3.36 (s, 2H, NCH2N), 3.05 (m, 2H,
2H, NCHCHPh), 2.89 (q, J ˆ 6.6 Hz, 2H, CHMe), 2.56 (d, J ˆ
ˆ
NCHCHN), 2.80 (m, 2H, CHCH CH2), 1.68 (br, 2H, NH), 1.35
6.2 Hz, 2H, NCHCHPh), 0.96 (d, J ˆ 6.6 Hz, 6H, CHMe).
(d, J ˆ 7.0 Hz, 6H, CHMe); MS: m/z (relative intensity) ˆ 105
(100), 173 (40), 278 (36), 69 (25), 79 (12), 106 (10), 345 (11).
1,3-Bis[1(S)-phenylethyl)]-4(R),5(R),6(S),9(R)-6,9-dieth-
enyl-2,3,4,5,6,9-hexahydro-1,3-diazaindene [(S,R)-7]: thick
yellow oil, yield: 95%; [a]2D0: À 72.6 (c 0.42, CHCl3); 1H NMR
(300 MHz, CDCl3): d ˆ 7.38 7.16 (m, 10H, Ph), 5.87 4.97 (m,
8H, vinyl), 4.13 and 3.66 (2 q, J ˆ 7.0 Hz, 2H, CHMe), 3.90 and
3.32 (2 d, J ˆ 6.3 Hz, 2H, NCH2N), 3.29 and 2.82 (2 m, 2H,
Acknowledgements
¡
Financial support from the Ministero dell×Universita e della
Ricerca Scientifica e Tecnologica, Roma, and The University of
Bologna (National Project ™Stereoselezione in Sintesi Organi-
ca. Metodologie e Applicazioni∫) is greatly acknowledged.
ˆ
CHCH CH2), 2.90 (dd, J ˆ 9.0 and 9.2 Hz, 1H, NCHCHN),
2.57 (dd, J ˆ 5.1 and 9.0 Hz, 1H, NCHCHN), 1.37 1.33 (2 d,
J ˆ 7.0, 6 H, CHMe); MS: m/z (relative intensity) ˆ 105 (100),
173 (23), 279 (21), 383 (19), 69 (16), 175 (16), 384 (13), 106 (12).
1,3-Bis[1(S)-phenylethyl)]-4(R),5(R)-di[1(S)-phenyl-2-pro-
penyl]imidazolidine (8): thick yellow oil, yield: 98%; 1H NMR
(300 MHz, CDCl3): d ˆ 7.20 (m, 16H, Ph), 6.98 (m, 4H, Ph),
References and Notes
[1] a) G. Alvaro, F. Grepioni, D. Savoia, J. Org. Chem. 1997,
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c) C. Fiorelli, L. Maini, G. Martelli, D. Savoia, C.
Zazzetta, Tetrahedron 2002, 58, in press.
ˆ
ˆ
5.99 (m, 2H, CH CH2), 5.05 and 4.86 (2 m, 4H, CH CH2), 3.54
(q, J ˆ 6.6 Hz, 2H, CHMe), 3.41 (s, 2H, NCH2N), 3.35 (d, J ˆ
7.8 Hz, 2H, NCHCHN), 2.84 (m, 2H, CHPh), 1.00 (d, J ˆ
6.6 Hz, CHMe).
[2] F. Grepioni, S. Grilli, G. Martelli, D. Savoia, J. Org.
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[3] Reviews: a) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc.
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Ring Closing Metathesis Reactions of Aminals 6 and 8
A solution of the aminal 6 (0.800 g, 1.94 mmol), trifluoroacetic
acid (0.44 g, 3.90 mmol) and the Grubbs× catalyst 4 (0.160 g,
0.2 mmol) in dry toluene (20 mL) was de-aerated by blowing
Ar for 5 min, then the reaction flask was placed in an oil bath,
whose temperature was raised to 120 8C, and reflux was
maintained for 3 h, then the mixture was allowed to cool in the
air overnight. Gaseous HCl was blown through the solution for
Adv. Synth. Catal. 2002, 344, 1068 1072
1071

Stefano Grilli et al.
COMMUNICATIONS
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[8] For an analogous example, the RCM reactions of 3,6-
dibenzyl-5-oxo-4-aza-1,7-octadiene could be achieved
only after the introduction of the 2,4-dimethoxybenzyl
N-substituent, allowing for the attainment of the syn-
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¬
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